Skip Navigation

Human Molecular Genetics 2005 14(Review Issue 1):R65-R76; doi:10.1093/hmg/ddi113
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Laird, P. W.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Laird, P. W.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org

Cancer epigenetics

Peter W. Laird*

Departments of Surgery and of Biochemistry and Molecular Biology, University of Southern California, Keck School of Medicine, Norris Comprehensive Cancer Center, Room 6418, 1441 Estlake Avenue, Los Angeles, CA 90089-9176, USA

* To whom correspondence should be addressed at: Tel: +1 323 8650650; Fax: +1 323 8650158; Email: plaird{at}usc.edu

Received January 21, 2005; Accepted February 24, 2005


   ABSTRACT
TOP
 ABSTRACT
INTEGRATED EPIGENETICS
 CAUSE AND EFFECT
 EPIGENETIC THERAPY
 EPIGENETIC DIAGNOSTICS
 EPIGENETIC CONTROL DEFECTS
 REFERENCES
 
The field of cancer epigenetics is evolving rapidly on several fronts. Advances in our understanding of chromatin structure, histone modification, transcriptional activity and DNA methylation have resulted in an increasingly integrated view of epigenetics. In response to these insights, epigenetic therapy is expanding to include combinations of histone deacetylase inhibitors and DNA methyltransferase inhibitors. Zebularine, an orally administerable DNA methyltransferase inhibitor, has been a very promising recent addition to our arsenal of potentially useful drugs for epigenetic therapy. Aberrant DNA methylation patterns provide three powerful diagnostic applications as classification markers, sensitive detection markers, and risk assessment markers. Classification studies continue to increase in marker complexity, now incorporating microarrays, high-throughput bisulfite genomic sequencing and mass spectrometry, as the field moves to human epigenome projects. Sensitive detection technology has expanded from primarily blood-based cancer detection to include applications on a wide diversity of sample sources and is now also making inroads as a molecular risk assessment tool.


   INTEGRATED EPIGENETICS
TOP
 ABSTRACT
 INTEGRATED EPIGENETICS
CAUSE AND EFFECT
 EPIGENETIC THERAPY
 EPIGENETIC DIAGNOSTICS
 EPIGENETIC CONTROL DEFECTS
 REFERENCES
 
Epigenetics refers to alternate phenotypic states that are not based in differences in genotype, and are potentially reversible, but are generally stably maintained during cell division. The narrow interpretation of this concept is that of stable differential states of gene expression. A much more expanded view of epigenetics has recently emerged in which multiple mechanisms interact to collectively establish alternate states of chromatin structure, histone modification, associated protein composition, transcriptional activity, and in mammals, cytosine-5 DNA methylation at CpG dinucleotides (1Go–4Go). It has long been known that cancer cells undergo changes in 5-methylcytosine distribution including global DNA hypomethylation (5Go) and the hypermethylation of promoter CpG islands associated with tumor-suppressor genes (6Go–9Go). It is now realized that CpG island hypermethylation is just one facet of an integrated change in chromatin structure and in histone modifications (10Go,11Go), including histone H3 and H4 deacetylation (12Go), histone H3 lysine 9 methylation (13Go), histone H4 sumoylation (14Go) and reduced histone H3 lysine 4 methylation (15Go,16Go), among others, collectively resulting in a transcriptionally silenced state (Fig. 1).



View larger version (35K):
[in this window]
[in a new window]
  		Figure 1. Epigenetic Silencing. Schematic of some of the molecular events that occur at CpG-rich promoters undergoing epigenetic silencing in cancer cells. The open chromatin structure of a transcriptionally active gene with loosely spaced nucleosomes (blue cylinders) is shown at the top and the transcriptionally silenced state with more tightly packed nucleosomes is shown at the bottom. DNA is indicated by a thin black line wrapped around nucleosomes. Proteins are indicated by shaded ovals, histone H3 acetylation is indicated by yellow triangles, hstone H3 methylation is indicated by orange hexagons and CpG dinucleotides are indicated by circles strung along the DNA, with green circles denoting an unmethylated state and red circles indicating a methylated state. Proteins involved in transcriptional activation are indicated in green (TF, tanscription factor; CO-ACT, co-activator; TBP, tata-binding factor; TAF, TBP-associated factor; RNA-PII, RNA polymerase II). Histone acetyl transferases (HAT) and histone deacetylases (HDAC) are indicated in yellow. Histone H3 lysine-4 (K4 HMT) and lysine-9 (K9-HMT) are indicated in orange. Proteins involved in transcriptional silencing are indicated in red (DNMT, DNA methyltransferase; MBD, methyl-binding domain protein; CO-REP, co-repressor; HP1, heterochromatin protein 1; CAF-1, chromatin assembly factor-1).

 
DNA methylation is a useful marker for assessing the epigenetic state of a locus, because it is preserved in purified isolated DNA, and can be measured by PCR-based techniques, but it should be realized that this is a one-dimensional measurement of a multidimensional state. Indeed, investigators have begun to incorporate an integrated analysis of epigenetic states in cancer cells (17Go,18Go) such as combinations of DNA methylation and transcription factor binding (19Go), gene expression and DNA methylation (20Go), DNA methylation and histone modifications (19Go,21Go), combinations of gene expression and DNA methylation with the use of epigenetic inhibitors (22Go–24Go) and also triple combinations of gene expression, DNA methylation and histone acetylation (25Go). In genetic studies, it has been found that an integrated analysis of genome-wide linkage analysis and gene expression can help to identify genetic determinants of quantitative traits (26Go). It is anticipated that the inclusion of genome-wide epigenetic analysis in similar studies will help to identify novel genetic and quantitative determinants of epigenetic states.


   CAUSE AND EFFECT
TOP
 ABSTRACT
 INTEGRATED EPIGENETICS
 CAUSE AND EFFECT
EPIGENETIC THERAPY
 EPIGENETIC DIAGNOSTICS
 EPIGENETIC CONTROL DEFECTS
 REFERENCES
 
Given the multidimensional character of epigenetic phenomena, the question arises, as to which mechanism is the driving force in systems undergoing epigenetic change. The cyclical nature of mutually reinforcing interactions makes this question challenging to address experimentally and renders its significance debatable. The concepts of cause and effect have clear meaning in linearly causal relationships, where necessary and sufficient components can be defined by adding and subtracting these elements from the system and where the temporal order of events may be clear. In a cyclically reinforcing system, the removal of any one component may affect all other elements, not just downstream components, and temporal relationships become less clear as all elements change in concert. Indeed, numerous reports documenting the antecedence or predominance of each of the main epigenetic mechanisms have been published. For example, histone deacetylation and histone H3 lysine 4 methylation precede DNA methylation and histone H3 lysine 9 methylation in some model systems (27Go), whereas Sp1 transcription factor binding appears to be an important block to epigenetic silencing in other systems (28Go). Nevertheless, DNA methylation can itself interfere with Sp1 binding (29Go) and can even attenuate transcription elongation (30Go). Consistent with this more pronounced role for DNA methylation, removal of transcription by promoter deletion appeared to have little effect on local DNA methylation patterns in some systems (31Go), whereas in others, removal of Sp1 binding sites was shown to be necessary, but not sufficient to achieve transcriptional silencing and CpG island hypermethylation (32Go). In this latter system, ‘seeding’ by sporadic CpG methylation was found to be an additional requirement for subsequent histone deacetylation, further spread of DNA methylation, MBD2 binding and histone H4 lysine 9 methylation (33Go). Other systems have also been reported to require a critical density of seeded DNA methylation for subsequent spreading and chromatin closure (34Go). In further support of the central role for DNA methylation in mammalian epigenetic control, maintenance of the developmentally regulated expression pattern of the human SERPINB5 gene has been shown to require DNA methylation (35Go), and aberrantly silenced genes in cancer cells can be transcriptionally activated by DNA methyltransferase inhibitors but not by histone deacetylase inhibitors alone (36Go–39Go). Moreover, in such inhibitor experiments, DNA demethylation occurs first, followed by transcriptional reactivation and subsequently histone code reversal (39Go). However, prolonged culture in the absence of inhibitor can lead to resilencing of gene expression and histone H3 lysine 9 methylation prior to the reacquisition of promoter DNA methylation (40Go). This distinction between the initial perturbation of an epigenetic state, and the reversal of that perturbation is nicely exemplified by the disruption of estrogen receptor signaling in human breast cancer cells, which results in stable repression of the progesterone receptor gene (41Go), accompanied by recruitment of polycomb repressors and histone deacetylases, and by promoter DNA methylation. However, merely reestablishing estrogen signaling was found to be insufficient to reactivate expression of the PR gene (41Go), indicating that, although loss of transcriptional activity triggered the epigenetic change, reversal of that event was no longer able to switch back the epigenetic state, once it had been established.

There are a few take-home lessons from these and other similar studies. First, perturbation of an existing epigenetic state may serve to show that a particular mechanism is required for maintenance of the epigenetic state, but does not necessarily imply that, under normal circumstances, this mechanism is the initiating event. Secondly, one has to be very careful about making sweeping generalizations based on observations with one particular system. However, there does appear to be a tendency towards change being initiated by transcriptional regulation or sequence-specific protein binding, associated with alterations in the histone code. In the case of epigenetic silencing, DNA methylation often appears late. However, once the silenced state has been achieved, DNA methylation appears to be a very powerful signal blocking reactivation of gene expression, regardless of perturbations to other parts of the system.


   EPIGENETIC THERAPY
TOP
 ABSTRACT
 INTEGRATED EPIGENETICS
 CAUSE AND EFFECT
 EPIGENETIC THERAPY
EPIGENETIC DIAGNOSTICS
 EPIGENETIC CONTROL DEFECTS
 REFERENCES
 
The potential reversibility of epigenetic states offers exciting opportunities for novel cancer drugs that can reactivate epigenetically silenced tumor-suppressor genes (12Go,42Go–44Go). Blocking either DNA methyltransferase or histone deacetylase activity could potentially inhibit or reverse the process of epigenetic silencing (Fig. 1). DNA methyltransferases and histone deacetylases are the two major drug targets for epigenetic inhibition to date, although others are expected to be added in the near future (Table 1). Most of the drugs with promising clinical prospects or those used widely as research tools are included in Table 1. Among those not listed are analogs of the methyl group donor S-adenosylmethionine, which inhibit a broad spectrum of cellular methyltransferases and have been shown to be potentially mutagenic (45Go). Although most reports on the inhibitors listed in Table 1 assume a high drug target specificity, many of these drugs in fact have pleiotropic effects. The most broadly used DNA methyltransferase inhibitor, 5-aza-2'-deoxycytidine (5-aza-CdR), clinically referred to as decitabine, has been shown to be have toxic effects aside from its demethylating properties (46Go) and has been found to be mutagenic in vivo (47Go). Moreover, 5-aza-CdR has been shown to be capable of transcriptionally activating genes with unmethylated promoters (48Go), also leading to increased acetylation and H3 lysine 4 methylation (37Go), suggesting this drug can induce chromatin remodeling independently of its effects on cytosine methylation. Gene expression microarray experiments confirmed that many genes activated by 5-aza-CdR lack promoter methylation, and for reasons that are not entirely clear, appear to be enriched for genes involved in interferon signaling (22Go–24Go,49Go–51Go). Similar studies have now also been performed using zebularine (52Go).


View this table:
[in this window]
[in a new window]
  		Table 1. Epigenetic inhibitors
 
The network of multiple reinforcing interactions involved in epigenetic silencing suggests that combination therapy would be a particularly appropriate strategy to achieve clinical efficacy (42Go–44Go). Indeed, combinations of DNA methyltransferase and histone deacetylase inhibitors appear to synergize effectively in the reactivation of epigenetically silenced genes (25Go,36Go,38Go,53Go,54Go). Combination trials are underway to test this concept in the clinic.

Several other exciting developments in epigenetic therapy have emerged recently. First, insight into the mode of action, the mechanism of toxicity and the pharmacokinetics of decitabine inspired an improved protocol with prolonged administration at lower doses, with equal, if not better efficacy than previous regimens (55Go). Toxicity has been one of the major problems with this drug and the efficacy of such low-dose protocols is an important advance. Even more exciting is the recent addition of zebularine to the arsenal of DNA methyltransferase inhibitors (56Go,57Go). In contrast to decitabine, zebularine is stable in aqueous solution and can be administered orally, greatly simplifying continuous low-dose therapy (56Go,58Go). Zebularine appears to be more effectively incorporated by cancer cells than by fibroblasts (57Go). Such a preferential response of cancer cells to epigenetic therapy is shared by decitabine (51Go) and histone deacetylase inhibitors (59Go), also in non-proliferating cancer cells, suggesting that epigenetic therapy could be an effective strategy for treating tumors with a low mitotic index (59Go).


   EPIGENETIC DIAGNOSTICS
TOP
 ABSTRACT
 INTEGRATED EPIGENETICS
 CAUSE AND EFFECT
 EPIGENETIC THERAPY
 EPIGENETIC DIAGNOSTICS
EPIGENETIC CONTROL DEFECTS
 REFERENCES
 
Epigenetic changes in cancer cells not only provide novel targets for drug therapy but also offer unique prospects for cancer diagnostics (60Go). The three main approaches to assess the epigenetic state of individual gene loci are to (1) measure gene expression, (2) determine histone modifications and chromatin protein composition and (3) analyze promoter DNA methylation status. Chromatin immunoprecipitation has been an extremely useful research tool to analyze chromatin protein composition and modifications. However, it has not advanced sufficiently yet to become a clinically useful diagnostic method, in contrast to serum proteomics by mass spectrometry, which is progressing rapidly in clinical feasibility studies (61Go). Gene expression microarray analysis has proved to be a powerful method for identifying novel subclasses of cancer and predicting clinical outcome or response to therapy (62Go,63Go). However, gene expression analysis is generally not viewed as epigenetic analysis, in part because mechanistic understanding of gene regulation evolved from studies of transcriptional control by transcription factors, which does not necessarily involve mitotically stable epigenetic change, although the fields of gene regulation and epigenetics are moving closer. The major interest in cancer epigenetics as a diagnostic tool is in localized epigenetic silencing. The use of gene expression microarray studies to identify non-transcribed genes as candidates for promoter CpG island hypermethylation has had limited success, because lack of gene expression can stem from other causes aside from epigenetic silencing (22Go–24Go,49Go–51Go). For the most part, cancer epigenetics has relied on measurements of CpG island DNA hypermethylation (7Go,60Go).

DNA methylation markers are used in cancer diagnostics for both disease classification and disease detection. As a classification tool, CpG island hypermethylation is generally analyzed on sufficient quantities of primary tissue such as a surgically resected tumor sample. The DNA methylation status of individual gene promoters can be used for general prognosis or to predict response to a particular therapy. There have been numerous reports describing an association between hypermethylation of individual genes and overall clinical outcome (prognosis) for various types of cancer (64Go–70Go). Individual methylation markers have also been linked to breast cancer metastasis (71Go). In particular, methylation of the E-cadherin (CDH1) promoter appears to be required for invasion and metastasis (72Go–75Go). It is more difficult to make a convincing case that a DNA methylation marker is a predictor of response to a specific therapy, and not just a general prognostic marker of clinical outcome, independent of therapy. One of the best cases has been made for hypermethylation of the O6-methylguanine methyltransferase (MGMT) promoter, which is associated with increased survival in glioma patients treated with alkylating agents (76Go–78Go). Melanoma cells with acquired resistance to the antineoplastic alkylating compound fotemustine, by repeated in vitro drug exposure, were shown to have reactivated the MGMT gene (79Go).

Increasingly, the profiling of a broader set of DNA methylation markers is used for prognosis and prediction, often facilitated by hierarchical cluster analysis (80Go). A screen of 10 genes in 145 neuroblastoma samples was able to delineate three main clinical risk groups (81Go), whereas a panel of 35 methylation markers revealed an association of DNA methylation profiles with hormone receptor status and response to tamoxifen treatment in 148 breast cancer patients (82Go). Unsupervised clustering of 956 unselected CpG islands in 19 late-stage ovarian tumors allowed discrimination between two major subgroups differing in progression-free survival rates (83Go). The increasing use of DNA methylation microarrays, high-throughput bisulfite genomic sequencing, mass spectrometry and other genome-wide techniques such as restriction landmark genome scanning is rapidly genomicizing epigenetics (25Go,84Go–87Go). A human epigenome project is now underway in Europe (88Go) (Murrell, this issue), and plans are being hatched for a similar effort in the USA. These molecular efforts are complemented by advances in epigenomic bioinformatics (80Go,89Go,90Go).

DNA methylation markers hold perhaps even greater promise as detectors of disease, as opposed to classifiers of existing disease (60Go). Disease detection is useful not only for the early detection of undiagnosed malignancies but also for the monitoring of recurrent disease as a measure of therapeutic efficacy (60Go). The demands placed on sensitive detection are quite different than those needed for the classification technology. Sensitive detection requires a high signal-to-noise ratio for the detection of aberrant DNA methylation patterns against a background of normal DNA methylation patterns. In principle, this can consist of the measurement of a single locus, although multiple loci may be needed to achieve sufficient sensitivity and specificity. Sensitive detection technologies tend to rely on sodium bisulfite-based methylation-specific PCR (MSP) to achieve sufficiently high signal-to-noise ratios (91Go). Molecular classification, on the other hand, requires that the methylation information is sufficiently complex that subclasses of DNA methylation patterns can be defined. Hence, the interest in microarray methods and other genome-wide techniques. However, these high-throughput methods are usually based on either methylation-sensitive restriction enzyme digestion or methylation-independent bisulfite PCR, as opposed to MSP, and have modest signal-to-noise ratios. Therefore, classification technologies usually require fairly homogeneous samples, such as primary tumor tissue, and are generally unsuited for sensitive detection purposes. Automated variants of MSP, such as the real-time PCR-based MethyLight technique (92Go), have both a sufficient signal-to-noise ratio and the throughput capacity to sensitively analyze a broad set of markers (82Go,93Go,94Go).

The use of DNA methylation markers to detect cancer sensitively is based on the premise that tumor-derived DNA is released into bodily fluids or other remote samples and can be detected by the abnormal DNA methylation patterns specific for malignant cells. Most studies have used serum or plasma as the source of cell-free DNA (60Go). However, in recent years, a number of other novel sources of DNA have been used including nipple aspirate fluid (95Go), breast fine needle washings (96Go), bronchial brush samples (97Go), needle biopsies (98Go), prostatic fluid or ejaculate (99Go,100Go), lymph nodes (101Go,102Go), bronchioalveolar lavage (103Go), pancreatic juice (104Go), sputum (105Go), mouth and throat rinsing fluid (106Go), exfoliated bladder cells (107Go), urine or urine sediments (108Go–111Go), peritoneal fluid (112Go,113Go), stool (93Go) and vaginal tampons (114Go,115Go).

As more types of samples are analyzed for a variety of different loci, it is becoming clear that epigenetic changes, including silencing of tumor-suppressor genes, may occur early in malignant progression and can sometimes be detected even in non-malignant or precancerous tissues. For example, promoter methylation of the p16INK4a (CDKN2A) gene is detectable in preinvasive bronchial lesions (116Go), in histologically normal human mammary epithelia (117Go) and in non-adenomatous pituitaries from patients with Cushing's disease (118Go). Promoter methylation of multiple genes has been reported in non-malignant gastric tissues (119Go–123Go), non-neoplastic prostate tissue (124Go,125Go), chronic cholecystitis (126Go) and ulcerative colitis (127Go). Some of these changes have been suggested to be age-related (121Go,127Go), whereas others have been proposed to be premalignant (123Go,128Go), in some cases associated with environmental risk exposures (129Go) and/or diet (130Go). The detection of epigenetic abnormalities in histologically normal or premalignant tissues at risk for progression to malignancy paves the way for the use of DNA methylation markers in risk assessment. Epigenetic markers should be particularly well suited as risk assessment tools, compared to germline genetic markers, because somatic epigenetic alterations presumably capture lifetime environmental and dietary exposures. Thus, a single class of markers can be used for assessing risk stemming from genotype and environmental exposure, for early detection of malignancy, and for classifying existing disease. In the next few years, the task will be to identify the markers and technologies best suited for each application. Moreover, if epigenetic changes occur in premalignant tissues, then this opens new avenues for cancer chemoprevention based on the inhibition or reversal of epigenetic alterations before the onset of malignancy (131Go).


   EPIGENETIC CONTROL DEFECTS
TOP
 ABSTRACT
 INTEGRATED EPIGENETICS
 CAUSE AND EFFECT
 EPIGENETIC THERAPY
 EPIGENETIC DIAGNOSTICS
 EPIGENETIC CONTROL DEFECTS
REFERENCES
 
The large estimated number of epigenetic alterations found in cancer cells (84Go,132Go) raises the question whether these reflect stochastic occurrences that accumulate with age, and are selected for during malignant outgrowth, or whether the large number of changes is caused by a defect in one of the components of the epigenetic machinery. By analogy, both stochastic mutations and mutator phenotypes are involved in producing the genetic alterations found in cancer. Likewise, it is anticipated that both stochastic errors and defects in epigenetic control participate in cancer epigenetics. The identification of these defects will likely emerge in the next few years as we acquire a fuller understanding of the normal mechanisms of maintenance and alteration of epigenetic states. Chromatin protein composition and histone modifications vary throughout the genome, with segregation maintained in part by chromatin insulators and boundaries (133Go–138Go) (West and Fraser, this issue). Therefore, it is likely that many epigenetic control defects will target a subset of genetic loci, rather than all loci equally. This has been modeled experimentally by overexpression of the DNMT1 DNA methyltransferase (139Go,140Go). Even this generic component of epigenetic control appeared to display locus specificity, leading to the identification of a set of putative DNA hypermethylation target consensus sequences with a striking purine/pyrimidine strand bias (141Go). Likewise, DNMT-deficient cells display distinct subsets of affected loci (24Go,142Go–145Go). Another nice example of the target specificity of an epigenetic control defect is the increased histone acetylation and transcriptional reactivation of repeat sequences and of the paternally imprinted allele of the Cdkn1c gene in cells deficient for the chromatin remodeling protein Lsh (146Go–148Go). Recent reports of transcriptional silencing and promoter DNA methylation induced by small interfering RNAs in human cells raise the interesting prospect of an involvement of microRNAs in epigenetic silencing in cancer cells (149Go,150Go) (Mattick, this issue).

One controversial putative epigenetic control defect is the CpG island methylator phenotype (CIMP) first reported in colorectal cancer (151Go), but since described for several other types of cancer as well (152Go). The essence of CIMP is the concerted hypermethylation of multiple CpG islands in a subset of cancer cases. The source of controversy stems from the fact that only a subset of CpG islands appears to be affected, primarily those that are cancer-specifically methylated. This is exactly the phenotype that one would predict for a cancer-specific epigenetic control defect, but an extensive study that included a broader analysis of CpG island hypermethylation failed to confirm the existence of CIMP (153Go), giving rise to heated debate concerning the existence of CIMP. Other groups have found associations between CIMP and various clinicopathological criteria in colorectal cancer including survival benefit from 5-FU treatment (154Go), genetic mutation profiles (155Go), location in the right-sided colon and microsatellite instability (156Go) and association with family history (157Go), although this could not be confirmed by another group (158Go).

Genetic predisposition and/or environmental exposures could lead to systemic epigenetic control defects that either increase the risk of developing cancer or at the very least represent surrogate markers for an increased risk. One such systemic epigenetic control defect appears to be loss of imprinting of the IGF2 locus, which occurs in the colorectal tumors, and in the normal colonic mucosa and white blood cells of individuals with colorectal cancer, or with a family history of colorectal cancer (159Go,160Go). If epigenetic control defects can occur systemically, then perhaps they can also contribute to cancer risk through transgenerational inheritance. Promoter methylation of the mismatch repair gene MLH1 is responsible for the majority of colorectal adenocarcinomas with microsatellite instability (161Go–164Go). This promoter methylation has been found to occur in normal colonic epithelium (165Go). Recently, strong evidence has accrued that MLH1 methylation can be transmitted through the germline, although true transgenerational inheritance in humans has not yet been formally demonstrated (166Go–168Go). Such transgenerational epigenetic inheritance has been well documented to occur in mice (169Go,170Go) (Ruden, this issue). Recently, paramutation, in which one allele can affect the epigenetic state of the other allele, has also been reported to occur in mice (171Go). It will be interesting to see if the mechanism responsible for this epigenetic cross-talk between alleles contributes to the biallelic CpG island hypermethylation frequently seen in cancer.

Mouse models of epigenetic control defects have been particularly useful in demonstrating the important contribution of epigenetics to tumorigenesis. A combination of Dnmt1 hypomorphic alleles and drug treatment was shown to severely inhibit tumor formation in ApcMin/+ mice which are predisposed to the development of intestinal adenomas (172Go). Subsequent work showed that both the size and growth rates of polyps were affected (173Go) and that a complete suppression of the tumor phenotype could be achieved without drug treatment by using more severe hypomorphic Dnmt1 alleles (174Go). In other words, intestinal polyp formation in this system is as much dependent on sufficient levels of functional Dnmt1 expression, as it is on the Apc mutation. These observations are consistent with a model in which polyp formation requires DNA methylation-dependent epigenetic silencing of unidentified tumor-suppressor genes, in addition to loss of heterozygosity of the wild-type Apc allele. Methyl-binding domain containing proteins (MBDs) bind to areas of dense DNA methylation and recruit histone deacetylases and transcriptional repressor complexes (Fig. 1). As such, MBDs are considered important mediators of epigenetic gene silencing, at the interface between DNA methylation and histone code modification. If the requirement of sufficient Dnmt1 expression for intestinal polyp formation is mediated through epigenetic silencing, then one would anticipate that polyp formation would also depend on other mediators of epigenetic silencing such as MBDs. In an elegant demonstration of the logical consistency of this proposed mechanism, ApcMin/+ mice deficient in Mbd2 were found to have substantially reduced numbers of intestinal polyps (175Go).

One of the criticisms of these mice model experiments has been that ApcMin/+ mice develop benign polyps, as opposed to malignant tumors (176Go). It has now been shown that malignant colorectal adenocarcinomas that arise in Mlh1–/– mice are also severely attenuated in Dnmt1 hypomorphic mice (177Go). However, interestingly, lymphomagenesis is increased in this same model (177Go). Increased lymphomagenesis in Dnmt1 hypomorphic mice was subsequently confirmed in mice without an Mlh1 mutation (178Go). Enhanced tumorigenesis in Dnmt1 hypomorphic mice was shown to be related to increased chromosomal instability (179Go). These findings are consistent with the previously reported increased mutation rates seen in Dnmt1-deficient mouse embryonic stem cells (180Go) and with the large body of literature describing associations between DNA hypomethylation, particularly of pericentromeric repeats and chromosomal instability in various human experimental and disease models (5Go,181Go–183Go). However, genomic instability can be attributed to multiple different mechanisms, not all of which may respond to DNA hypomethylation or DNMT1 deficiency in equal ways. Indeed, others have reported that Dnmt1 deficiency can result in a reduced mutation and deletion rate in embryonic stem cells (184Go), consistent with the important contribution of 5-methylcytosine to deamination-mediated mutagenesis in mammalian cells. The diverse roles that Dnmt1 and DNA methylation play in the maintenance of genomic integrity has been further emphasized by the recent discovery that Dnmt1 is required for efficient DNA mismatch repair and that rates of microsatellite instability increase under Dnmt1-deficient conditions (185Go–188Go).

It is clear from this bird's-eye overview that the field of cancer epigenetics is in flux. We can expect to see clinical implementation of both epigenetic cancer therapy and epigenetic cancer diagnostics in the next decade. Epigenetic control defects in cancer cells represent an emerging new area of investigation, where significant breakthroughs in the identification of the underlying molecular defects are anticipated in the next few years.


   ACKNOWLEDGEMENTS
 
The cancer epigenetics work in the author's laboratory is supported by NIH grants R21-ES-11672, R01-CA-096958, R01-CA-001815 and R01-CA-075090 to P.W.L.


   REFERENCES
TOP
 ABSTRACT
 INTEGRATED EPIGENETICS
 CAUSE AND EFFECT
 EPIGENETIC THERAPY
 EPIGENETIC DIAGNOSTICS
 EPIGENETIC CONTROL DEFECTS
 REFERENCES
 

  1. Ordway, J.M. and Curran, T. (2002) Methylation matters: modeling a manageable genome. Cell Growth Differ. 13, 149–162.[Free Full Text]

  2. Freiman, R.N. and Tjian, R. (2003) Regulating the regulators: lysine modifications make their mark. Cell, 112, 11–17.[CrossRef][Web of Science][Medline]

  3. Felsenfeld, G. and Groudine, M. (2003) Controlling the double helix. Nature, 421, 448–453.[CrossRef][Medline]

  4. Jaenisch, R. and Bird, A. (2003) Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat. Genet., 33, 245–254.

  5. Ehrlich, M. (2002) DNA methylation in cancer: too much, but also too little. Oncogene, 21, 5400–5413.[CrossRef][Web of Science][Medline]

  6. Jones, P.A. and Laird, P.W. (1999) Cancer epigenetics comes of age. Nat. Genet., 21, 163–167.[CrossRef][Web of Science][Medline]

  7. Herman, J.G. and Baylin, S.B. (2003) Gene silencing in cancer in association with promoter hypermethylation. N. Engl. J. Med., 349, 2042–2054.[Free Full Text]

  8. Esteller, M. (2002) CpG island hypermethylation and tumor suppressor genes: a booming present, a brighter future. Oncogene, 21, 5427–5440.[CrossRef][Web of Science][Medline]

  9. Bird, A.P. (1996) The relationship of DNA methylation to cancer. Cancer Surv., 28, 87–101.[Web of Science][Medline]

  10. Jones, P.A. and Baylin, S.B. (2002) The fundamental role of epigenetic events in cancer. Nat. Rev. Genet., 3, 415–428.[Web of Science][Medline]

  11. Lund, A.H. and van Lohuizen, M. (2004) Epigenetics and cancer. Genes Dev., 18, 2315–2335.[Abstract/Free Full Text]

  12. Johnstone, R.W. (2002) Histone-deacetylase inhibitors: novel drugs for the treatment of cancer. Nat. Rev. Drug Discov., 1, 287–299.[CrossRef][Web of Science][Medline]

  13. Kondo, Y., Shen, L. and Issa, J.P. (2003) Critical role of histone methylation in tumor suppressor gene silencing in colorectal cancer. Mol. Cell. Biol., 23, 206–215.[Abstract/Free Full Text]

  14. Shiio, Y. and Eisenman, R.N. (2003) Histone sumoylation is associated with transcriptional repression. Proc. Natl Acad. Sci. USA, 100, 13225–13230.[Abstract/Free Full Text]

  15. Liang, G., Lin, J.C., Wei, V., Yoo, C., Cheng, J.C., Nguyen, C.T., Weisenberger, D.J., Egger, G., Takai, D., Gonzales, F.A. et al. (2004) Distinct localization of histone H3 acetylation and H3-K4 methylation to the transcription start sites in the human genome. Proc. Natl Acad. Sci. USA, 101, 7357–7362.[Abstract/Free Full Text]

  16. Boggs, B.A., Cheung, P., Heard, E., Spector, D.L., Chinault, A.C. and Allis, C.D. (2002) Differentially methylated forms of histone H3 show unique association patterns with inactive human X chromosomes. Nat. Genet., 30, 73–76.[CrossRef][Web of Science][Medline]

  17. Hanash, S. (2004) Integrated global profiling of cancer. Nat. Rev. Cancer, 4, 638–644.[CrossRef][Web of Science][Medline]

  18. Zardo, G., Tiirikainen, M.I., Hong, C., Misra, A., Feuerstein, B.G., Volik, S., Collins, C.C., Lamborn, K.R., Bollen, A., Pinkel, D. et al. (2002) Integrated genomic and epigenomic analyses pinpoint biallelic gene inactivation in tumors. Nat. Genet., 32, 453–458.[CrossRef][Web of Science][Medline]

  19. Weinmann, A.S., Yan, P.S., Oberley, M.J., Huang, T.H. and Farnham, P.J. (2002) Isolating human transcription factor targets by coupling chromatin immunoprecipitation and CpG island microarray analysis. Genes Dev., 16, 235–244.[Abstract/Free Full Text]

  20. Mori, Y., Yin, J., Sato, F., Sterian, A., Simms, L.A., Selaru, F.M., Schulmann, K., Xu, Y., Olaru, A., Wang, S. et al. (2004) Identification of genes uniquely involved in frequent microsatellite instability colon carcinogenesis by expression profiling combined with epigenetic scanning. Cancer Res., 64, 2434–2438.[Abstract/Free Full Text]

  21. Nouzova, M., Holtan, N., Oshiro, M.M., Isett, R.B., Munoz-Rodriguez, J.L., List, A.F., Narro, M.L., Miller, S.J., Merchant, N.C. and Futscher, B.W. (2004) Epigenomic changes during leukemia cell differentiation: analysis of histone acetylation and cytosine methylation using CpG island microarrays. J. Pharmacol. Exp. Ther., 311, 968–981.[Abstract/Free Full Text]

  22. Suzuki, H., Gabrielson, E., Chen, W., Anbazhagan, R., van Engeland, M., Weijenberg, M.P., Herman, J.G. and Baylin, S.B. (2002) A genomic screen for genes upregulated by demethylation and histone deacetylase inhibition in human colorectal cancer. Nat. Genet., 31, 141–149.[CrossRef][Web of Science][Medline]

  23. Liang, G., Gonzales, F.A., Jones, P.A., Orntoft, T.F. and Thykjaer, T. (2002) Analysis of gene induction in human fibroblasts and bladder cancer cells exposed to the methylation inhibitor 5-aza-2'-deoxycytidine. Cancer Res., 62, 961–966.[Abstract/Free Full Text]

  24. Gius, D., Cui, H., Bradbury, C.M., Cook, J., Smart, D.K., Zhao, S., Young, L., Brandenburg, S.A., Hu, Y., Bisht, K.S. et al. (2004) Distinct effects on gene expression of chemical and genetic manipulation of the cancer epigenome revealed by a multimodality approach. Cancer Cell, 6, 361–371.[CrossRef][Web of Science][Medline]

  25. Shi, H., Wei, S.H., Leu, Y.W., Rahmatpanah, F., Liu, J.C., Yan, P.S., Nephew, K.P. and Huang, T.H. (2003) Triple analysis of the cancer epigenome: an integrated microarray system for assessing gene expression, DNA methylation, and histone acetylation. Cancer Res., 63, 2164–2171.[Abstract/Free Full Text]

  26. Morley, M., Molony, C.M., Weber, T.M., Devlin, J.L., Ewens, K.G., Spielman, R.S. and Cheung, V.G. (2004) Genetic analysis of genome-wide variation in human gene expression. Nature, 430, 743–747.[CrossRef][Medline]

  27. Mutskov, V. and Felsenfeld, G. (2004) Silencing of transgene transcription precedes methylation of promoter DNA and histone H3 lysine 9. EMBO J., 23, 138–149.[CrossRef][Web of Science][Medline]

  28. Mummaneni, P., Yates, P., Simpson, J., Rose, J. and Turker, M.S. (1998) The primary function of a redundant Sp1 binding site in the mouse aprt gene promoter is to block epigenetic gene inactivation. Nucleic Acids Res., 26, 5163–5169.[Abstract/Free Full Text]

  29. Zhu, W.G., Srinivasan, K., Dai, Z., Duan, W., Druhan, L.J., Ding, H., Yee, L., Villalona-Calero, M.A., Plass, C. and Otterson, G.A. (2003) Methylation of adjacent CpG sites affects Sp1/Sp3 binding and activity in the p21(Cip1) promoter. Mol. Cell. Biol., 23, 4056–4065.[Abstract/Free Full Text]

  30. Lorincz, M.C., Dickerson, D.R., Schmitt, M. and Groudine, M. (2004) Intragenic DNA methylation alters chromatin structure and elongation efficiency in mammalian cells. Nat. Struct. Mol. Biol., 11, 1068–1075.[CrossRef][Web of Science][Medline]

  31. Kang, S.H., Kiefer, C.M. and Yang, T.P. (2003) Role of the promoter in maintaining transcriptionally active chromatin structure and DNA methylation patterns in vivo. Mol. Cell. Biol., 23, 4150–4161.

  32. Song, J.Z., Stirzaker, C., Harrison, J., Melki, J.R. and Clark, S.J. (2002) Hypermethylation trigger of the glutathione-S-transferase gene (GSTP1) in prostate cancer cells. Oncogene, 21, 1048–1061.[CrossRef][Web of Science][Medline]

  33. Stirzaker, C., Song, J.Z., Davidson, B. and Clark, S.J. (2004) Transcriptional gene silencing promotes DNA hypermethylation through a sequential change in chromatin modifications in cancer cells. Cancer Res., 64, 3871–3877.[Abstract/Free Full Text]

  34. Lorincz, M.C., Schubeler, D., Hutchinson, S.R., Dickerson, D.R. and Groudine, M. (2002) DNA methylation density influences the stability of an epigenetic imprint and Dnmt3a/b-independent de novo methylation. Mol. Cell. Biol., 22, 7572–7580.[Abstract/Free Full Text]

  35. Futscher, B.W., Oshiro, M.M., Wozniak, R.J., Holtan, N., Hanigan, C.L., Duan, H. and Domann, F.E. (2002) Role for DNA methylation in the control of cell type specific maspin expression. Nat. Genet., 31, 175–179.[CrossRef][Web of Science][Medline]

  36. Cameron, E.E., Bachman, K.E., Myohanen, S., Herman, J.G. and Baylin, S.B. (1999) Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer. Nat. Genet., 21, 103–107.[CrossRef][Web of Science][Medline]

  37. Nguyen, C.T., Weisenberger, D.J., Velicescu, M., Gonzales, F.A., Lin, J.C., Liang, G. and Jones, P.A. (2002) Histone H3-lysine 9 methylation is associated with aberrant gene silencing in cancer cells and is rapidly reversed by 5-aza-2'- deoxycytidine. Cancer Res., 62, 6456–6461.[Abstract/Free Full Text]

  38. Yang, X., Phillips, D.L., Ferguson, A.T., Nelson, W.G., Herman, J.G. and Davidson, N.E. (2001) Synergistic activation of functional estrogen receptor (ER)-alpha by DNA methyltransferase and histone deacetylase inhibition in human ER-alpha-negative breast cancer cells. Cancer Res., 61, 7025–7029.[Abstract/Free Full Text]

  39. Fahrner, J.A., Eguchi, S., Herman, J.G. and Baylin, S.B. (2002) Dependence of histone modifications and gene expression on DNA hypermethylation in cancer. Cancer Res., 62, 7213–7218.[Abstract/Free Full Text]

  40. Bachman, K.E., Park, B.H., Rhee, I., Rajagopalan, H., Herman, J.G., Baylin, S.B., Kinzler, K.W. and Vogelstein, B. (2003) Histone modifications and silencing prior to DNA methylation of a tumor suppressor gene. Cancer Cell, 3, 89–95.[CrossRef][Web of Science][Medline]

  41. Leu, Y.W., Yan, P.S., Fan, M., Jin, V.X., Liu, J.C., Curran, E.M., Welshons, W.V., Wei, S.H., Davuluri, R.V., Plass, C. et al. (2004) Loss of estrogen receptor signaling triggers epigenetic silencing of downstream targets in breast cancer. Cancer Res., 64, 8184–8192.[Abstract/Free Full Text]

  42. Egger, G., Liang, G., Aparicio, A. and Jones, P.A. (2004) Epigenetics in human disease and prospects for epigenetic therapy. Nature, 429, 457–463.[CrossRef][Medline]

  43. Esteller, M. (2005) DNA methylation and cancer therapy: new developments and expectations. Curr. Opin. Oncol., 17, 55–60.[CrossRef][Web of Science][Medline]

  44. Zelent, A., Waxman, S., Carducci, M., Wright, J., Zweibel, J. and Gore, S.D. (2004) State of the translational science: summary of Baltimore workshop on gene re-expression as a therapeutic target in cancer January 2003. Clin. Cancer Res., 10, 4622–4629.[Abstract/Free Full Text]

  45. Zingg, J.M., Shen, J.C., Yang, A.S., Rapoport, H. and Jones, P.A. (1996) Methylation inhibitors can increase the rate of cytosine deamination by (cytosine-5)-DNA methyltransferase. Nucleic Acids Res., 24, 3267–3275.[Abstract/Free Full Text]

  46. Juttermann, R., Li, E. and Jaenisch, R. (1994) Toxicity of 5-aza-2'-deoxycytidine to mammalian cells is mediated primarily by covalent trapping of DNA methyltransferase rather than DNA demethylation. Proc. Natl Acad. Sci. USA, 91, 11797–11801.

  47. Jackson-Grusby, L., Laird, P.W., Magge, S.N., Moeller, B.J. and Jaenisch, R. (1997) Mutagenicity of 5-aza-2'-deoxycytidine is mediated by the mammalian DNA methyltransferase. Proc. Natl Acad. Sci. USA., 94, 4681–4685.[Abstract/Free Full Text]

  48. Soengas, M.S., Capodieci, P., Polsky, D., Mora, J., Esteller, M., Opitz-Araya, X., McCombie, R., Herman, J.G., Gerald, W.L., Lazebnik, Y.A. et al. (2001) Inactivation of the apoptosis effector Apaf-1 in malignant melanoma. Nature, 409, 207–211.[CrossRef][Medline]

  49. Karpf, A.R., Peterson, P.W., Rawlins, J.T., Dalley, B.K., Yang, Q., Albertsen, H. and Jones, D.A. (1999) Inhibition of DNA methyltransferase stimulates the expression of signal transducer and activator of transcription 1, 2, and 3 genes in colon tumor cells. Proc. Natl Acad. Sci. USA, 96, 14007–14012.[Abstract/Free Full Text]

  50. Kulaeva, O.I., Draghici, S., Tang, L., Kraniak, J.M., Land, S.J. and Tainsky, M.A. (2003) Epigenetic silencing of multiple interferon pathway genes after cellular immortalization. Oncogene, 22, 4118–4127.[CrossRef][Web of Science][Medline]

  51. Schmelz, K., Sattler, N., Wagner, M., Lubbert, M., Dorken, B. and Tamm, I. (2005) Induction of gene expression by 5-aza-2'-deoxycytidine in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) but not epithelial cells by DNA-methylation-dependent and -independent mechanisms. Leukemia, 19, 103–111.[Web of Science][Medline]

  52. Pompeia, C., Hodge, D.R., Plass, C., Wu, Y.Z., Marquez, V.E., Kelley, J.A. and Farrar, W.L. (2004) Microarray analysis of epigenetic silencing of gene expression in the KAS-6/1 multiple myeloma cell line. Cancer Res., 64, 3465–3473.[Abstract/Free Full Text]

  53. Bovenzi, V. and Momparler, R.L. (2001) Antineoplastic action of 5-aza-2'-deoxycytidine and histone deacetylase inhibitor and their effect on the expression of retinoic acid receptor beta and estrogen receptor alpha genes in breast carcinoma cells. Cancer Chemother. Pharmacol., 48, 71–76.[CrossRef][Web of Science][Medline]

  54. Belinsky, S.A., Klinge, D.M., Stidley, C.A., Issa, J.P., Herman, J.G., March, T.H. and Baylin, S.B. (2003) Inhibition of DNA methylation and histone deacetylation prevents murine lung cancer. Cancer Res., 63, 7089–7093.[Abstract/Free Full Text]

  55. Issa, J.P., Garcia-Manero, G., Giles, F.J., Mannari, R., Thomas, D., Faderl, S., Bayar, E., Lyons, J., Rosenfeld, C.S., Cortes, J. et al. (2004) Phase 1 study of low-dose prolonged exposure schedules of the hypomethylating agent 5-aza-2'-deoxycytidine (decitabine) in hematopoietic malignancies. Blood, 103, 1635–1640.[Abstract/Free Full Text]

  56. Cheng, J.C., Matsen, C.B., Gonzales, F.A., Ye, W., Greer, S., Marquez, V.E., Jones, P.A. and Selker, E.U. (2003) Inhibition of DNA methylation and reactivation of silenced genes by zebularine. J. Natl Cancer Inst., 95, 399–409.[Abstract/Free Full Text]

  57. Cheng, J.C., Yoo, C.B., Weisenberger, D.J., Chuang, J., Wozniak, C., Liang, G., Marquez, V.E., Greer, S., Orntoft, T.F., Thykjaer, T. et al. (2004) Preferential response of cancer cells to zebularine. Cancer Cell, 6, 151–158.[CrossRef][Web of Science][Medline]

  58. Cheng, J.C., Weisenberger, D.J., Gonzales, F.A., Liang, G., Xu, G.L., Hu, Y.G., Marquez, V.E. and Jones, P.A. (2004) Continuous zebularine treatment effectively sustains demethylation in human bladder cancer cells. Mol. Cell. Biol., 24, 1270–1278.[Abstract/Free Full Text]

  59. Burgess, A., Ruefli, A., Beamish, H., Warrener, R., Saunders, N., Johnstone, R. and Gabrielli, B. (2004) Histone deacetylase inhibitors specifically kill nonproliferating tumour cells. Oncogene, 23, 6693–6701.[CrossRef][Web of Science][Medline]

  60. Laird, P.W. (2003) The power and the promise of DNA methylation markers. Nat. Rev. Cancer, 3, 253–266.[CrossRef][Web of Science][Medline]

  61. Wulfkuhle, J.D., Liotta, L.A. and Petricoin, E.F. (2003) Proteomic applications for the early detection of cancer. Nat. Rev. Cancer, 3, 267–275.[CrossRef][Web of Science][Medline]

  62. Ramaswamy, S., Tamayo, P., Rifkin, R., Mukherjee, S., Yeang, C.H., Angelo, M., Ladd, C., Reich, M., Latulippe, E., Mesirov, J.P. et al. (2001) Multiclass cancer diagnosis using tumor gene expression signatures. Proc. Natl Acad. Sci. USA, 98, 15149–15154.[Abstract/Free Full Text]

  63. van 't Veer, L.J., Dai, H., van de Vijver, M.J., He, Y.D., Hart, A.A., Mao, M., Peterse, H.L., van der Kooy, K., Marton, M.J., Witteveen, A.T. et al. (2002) Gene expression profiling predicts clinical outcome of breast cancer. Nature, 415, 530–536.[CrossRef][Medline]

  64. Graziano, F., Arduini, F., Ruzzo, A., Bearzi, I., Humar, B., More, H., Silva, R., Muretto, P., Guilford, P., Testa, E. et al. (2004) Prognostic analysis of E-cadherin gene promoter hypermethylation in patients with surgically resected, node-positive, diffuse gastric cancer. Clin. Cancer Res., 10, 2784–2789.[Abstract/Free Full Text]

  65. Toyooka, S., Suzuki, M., Maruyama, R., Toyooka, K.O., Tsukuda, K., Fukuyama, Y., Iizasa, T., Aoe, M., Date, H., Fujisawa, T. et al. (2004) The relationship between aberrant methylation and survival in non-small-cell lung cancers. Br. J. Cancer, 91, 771–774.[Web of Science][Medline]

  66. Roman-Gomez, J., Jimenez-Velasco, A., Castillejo, J.A., Agirre, X., Barrios, M., Navarro, G., Molina, F.J., Calasanz, M.J., Prosper, F., Heiniger, A. et al. (2004) Promoter hypermethylation of cancer-related genes: a strong independent prognostic factor in acute lymphoblastic leukemia. Blood, 104, 2492–2498.[Abstract/Free Full Text]

  67. Brock, M.V., Gou, M., Akiyama, Y., Muller, A., Wu, T.T., Montgomery, E., Deasel, M., Germonpre, P., Rubinson, L., Heitmiller, R.F. et al. (2003) Prognostic importance of promoter hypermethylation of multiple genes in esophageal adenocarcinoma. Clin. Cancer Res., 9, 2912–2919.[Abstract/Free Full Text]

  68. Fruhwald, M.C. (2003) DNA methylation patterns in cancer: novel prognostic indicators? Am. J. Pharmacogenomics, 3, 245–260.[CrossRef][Medline]

  69. Gerdes, B., Ramaswamy, A., Ziegler, A., Lang, S.A., Kersting, M., Baumann, R., Wild, A., Moll, R., Rothmund, M. and Bartsch, D.K. (2002) p16INK4a is a prognostic marker in resected ductal pancreatic cancer: an analysis of p16INK4a, p53, MDM2, an Rb. Ann. Surg., 235, 51–59.[CrossRef][Web of Science][Medline]

  70. Esteller, M., Gonzalez, S., Risques, R.A., Marcuello, E., Mangues, R., Germa, J.R., Herman, J.G., Capella, G. and Peinado, M.A. (2001) K-ras and p16 aberrations confer poor prognosis in human colorectal cancer. J. Clin. Oncol., 19, 299–304.[Abstract/Free Full Text]

  71. Mehrotra, J., Vali, M., McVeigh, M., Kominsky, S.L., Fackler, M.J., Lahti-Domenici, J., Polyak, K., Sacchi, N., Garrett-Mayer, E., Argani, P. et al. (2004) Very high frequency of hypermethylated genes in breast cancer metastasis to the bone, brain, and lung. Clin. Cancer Res., 10, 3104–3109.[Abstract/Free Full Text]

  72. Kudo, Y., Kitajima, S., Ogawa, I., Hiraoka, M., Sargolzaei, S., Keikhaee, M.R., Sato, S., Miyauchi, M. and Takata, T. (2004) Invasion and metastasis of oral cancer cells require methylation of E-cadherin and/or degradation of membranous beta-catenin. Clin. Cancer Res., 10, 5455–5463.[Abstract/Free Full Text]

  73. Graff, J.R., Gabrielson, E., Fujii, H., Baylin, S.B. and Herman, J.G. (2000) Methylation patterns of the E-cadherin 5' CpG island are unstable and reflect the dynamic, heterogeneous loss of E-cadherin expression during metastatic progression. J. Biol. Chem., 275, 2727–2732.[Abstract/Free Full Text]

  74. Di Croce, L. and Pelicci, P.G. (2003) Tumour-associated hypermethylation: silencing E-cadherin expression enhances invasion and metastasis. Eur. J. Cancer, 39, 413–414.

  75. Azarschab, P., Stembalska, A., Loncar, M.B., Pfister, M., Sasiadek, M.M. and Blin, N. (2003) Epigenetic control of E-cadherin (CDH1) by CpG methylation in metastasising laryngeal cancer. Oncol. Rep., 10, 501–503.[Web of Science][Medline]

  76. Esteller, M., Garcia-Foncillas, J., Andion, E., Goodman, S.N., Hidalgo, O.F., Vanaclocha, V., Baylin, S.B. and Herman, J.G. (2000) Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents. N. Engl. J. Med., 343, 1350–1354.[Abstract/Free Full Text]

  77. Hegi, M.E., Diserens, A.C., Godard, S., Dietrich, P.Y., Regli, L., Ostermann, S., Otten, P., Van Melle, G., de Tribolet, N. and Stupp, R. (2004) Clinical trial substantiates the predictive value of O-6-methylguanine-DNA methyltransferase promoter methylation in glioblastoma patients treated with temozolomide. Clin. Cancer Res., 10, 1871–1874.[Abstract/Free Full Text]

  78. Paz, M.F., Yaya-Tur, R., Rojas-Marcos, I., Reynes, G., Pollan, M., Aguirre-Cruz, L., Garcia-Lopez, J.L., Piquer, J., Safont, M.J., Balana, C. et al. (2004) CpG island hypermethylation of the DNA repair enzyme methyltransferase predicts response to temozolomide in primary gliomas. Clin. Cancer Res., 10, 4933–4938.[Abstract/Free Full Text]

  79. Christmann, M., Pick, M., Lage, H., Schadendorf, D. and Kaina, B. (2001) Acquired resistance of melanoma cells to the antineoplastic agent fotemustine is caused by reactivation of the DNA repair gene MGMT. Int. J. Cancer, 92, 123–129.[CrossRef][Web of Science][Medline]

  80. Siegmund, K.D., Laird, P.W. and Laird-Offringa, I.A. (2004) A comparison of cluster analysis methods using DNA methylation data. Bioinformatics, 25, 25.

  81. Alaminos, M., Davalos, V., Cheung, N.K., Gerald, W.L. and Esteller, M. (2004) Clustering of gene hypermethylation associated with clinical risk groups in neuroblastoma. J. Natl Cancer Inst., 96, 1208–1219.[Abstract/Free Full Text]

  82. Widschwendter, M., Siegmund, K.D., Muller, H.M., Fiegl, H., Marth, C., Muller-Holzner, E., Jones, P.A. and Laird, P.W. (2004) Association of breast cancer DNA methylation profiles with hormone receptor status and response to tamoxifen. Cancer Res., 64, 3807–3813.[Abstract/Free Full Text]

  83. Wei, S.H., Chen, C.M., Strathdee, G., Harnsomburana, J., Shyu, C.R., Rahmatpanah, F., Shi, H., Ng, S.W., Yan, P.S., Nephew, K.P. et al. (2002) Methylation microarray analysis of late-stage ovarian carcinomas distinguishes progression-free survival in patients and identifies candidate epigenetic markers. Clin. Cancer Res., 8, 2246–2252.[Abstract/Free Full Text]

  84. Costello, J.F., Fruhwald, M.C., Smiraglia, D.J., Rush, L.J., Robertson, G.P., Gao, X., Wright, F.A., Feramisco, J.D., Peltomaki, P., Lang, J.C. et al. (2000) Aberrant CpG-island methylation has non-random and tumour-type-specific patterns. Nat. Genet., 24, 132–138.[CrossRef][Web of Science][Medline]

  85. Rush, D. (1994) Periconceptional folate and neural tube defect. Am. J. Clin. Nutr., 59, 515S–516S.

  86. Beck, S., Olek, A. and Walter, J. (1999) From genomics to epigenomics: a loftier view of life. Nat. Biotechnol., 17, 1144.[CrossRef][Web of Science][Medline]

  87. Adorjan, P., Distler, J., Lipscher, E., Model, F., Muller, J., Pelet, C., Braun, A., Florl, A.R., Gutig, D., Grabs, G. et al. (2002) Tumour class prediction and discovery by microarray-based DNA methylation analysis. Nucleic Acids Res., 30, E21.

  88. Rakyan, V.K., Hildmann, T., Novik, K.L., Lewin, J., Tost, J., Cox, A.V., Andrews, T.D., Howe, K.L., Otto, T., Olek, A. et al. (2004) DNA methylation profiling of the human major histocompatibility complex: a pilot study for the human epigenome project. PLoS Biol., 2, E405.

  89. Fazzari, M.J. and Greally, J.M. (2004) Epigenomics: beyond CpG islands. Nat. Rev. Genet., 5, 446–455.[CrossRef][Web of Science][Medline]

  90. Model, F., Adorjan, P., Olek, A. and Piepenbrock, C. (2001) Feature selection for DNA methylation based cancer classification. Bioinformatics, 17, S157–S164.[Abstract]

  91. Herman, J.G., Graff, J.R., Myohanen, S., Nelkin, B.D. and Baylin, S.B. (1996) Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc. Natl Acad. Sci. USA, 93, 9821–9826.[Abstract/Free Full Text]

  92. Eads, C.A., Danenberg, K.D., Kawakami, K., Saltz, L.B., Blake, C., Shibata, D., Danenberg, P.V. and Laird, P.W. (2000) MethyLight: a high-throughput assay to measure DNA methylation. Nucleic Acids Res., 28, E32.

  93. Muller, H.M., Oberwalder, M., Fiegl, H., Morandell, M., Goebel, G., Zitt, M., Muhlthaler, M., Ofner, D., Margreiter, R. and Widschwendter, M. (2004) Methylation changes in faecal DNA: a marker for colorectal cancer screening? Lancet, 363, 1283–1285.[CrossRef][Web of Science][Medline]

  94. Muller, H.M., Widschwendter, A., Fiegl, H., Ivarsson, L., Goebel, G., Perkmann, E., Marth, C. and Widschwendter, M. (2003) DNA methylation in serum of breast cancer patients: an independent prognostic marker. Cancer Res., 63, 7641–7645.[Abstract/Free Full Text]

  95. Krassenstein, R., Sauter, E., Dulaimi, E., Battagli, C., Ehya, H., Klein-Szanto, A. and Cairns, P. (2004) Detection of breast cancer in nipple aspirate fluid by CpG island hypermethylation. Clin. Cancer Res., 10, 28–32.[CrossRef][Web of Science][Medline]

  96. Jeronimo, C., Costa, I., Martins, M.C., Monteiro, P., Lisboa, S., Palmeira, C., Henrique, R., Teixeira, M.R. and Lopes, C. (2003) Detection of gene promoter hypermethylation in fine needle washings from breast lesions. Clin. Cancer Res., 9, 3413–3417.[Abstract/Free Full Text]

  97. Soria, J.C., Rodriguez, M., Liu, D.D., Lee, J.J., Hong, W.K. and Mao, L. (2002) Aberrant promoter methylation of multiple genes in bronchial brush samples from former cigarette smokers. Cancer Res., 62, 351–355.[Abstract/Free Full Text]

  98. Tokumaru, Y., Harden, S.V., Sun, D.I., Yamashita, K., Epstein, J.I. and Sidransky, D. (2004) Optimal use of a panel of methylation markers with GSTP1 hypermethylation in the diagnosis of prostate adenocarcinoma. Clin. Cancer Res., 10, 5518–5522.[Abstract/Free Full Text]

  99. Gonzalgo, M.L., Nakayama, M., Lee, S.M., De Marzo, A.M. and Nelson, W.G. (2004) Detection of GSTP1 methylation in prostatic secretions using combinatorial MSP analysis. Urology, 63, 414–418.[CrossRef][Web of Science][Medline]

  100. Goessl, C., Krause, H., Muller, M., Heicappell, R., Schrader, M., Sachsinger, J. and Miller, K. (2000) Fluorescent methylation-specific polymerase chain reaction for DNA-based detection of prostate cancer in bodily fluids. Cancer Res., 60, 5941–5945.[Abstract/Free Full Text]

  101. Harden, S.V., Tokumaru, Y., Westra, W.H., Goodman, S., Ahrendt, S.A., Yang, S.C. and Sidransky, D. (2003) Gene promoter hypermethylation in tumors and lymph nodes of stage I lung cancer patients. Clin. Cancer Res., 9, 1370–1375.[Abstract/Free Full Text]

  102. Pellise, M., Castells, A., Gines, A., Agrelo, R., Sole, M., Castellvi-Bel, S., Fernandez-Esparrach, G., Llach, J., Esteller, M., Bordas, J.M. et al. (2004) Detection of lymph node micrometastases by gene promoter hypermethylation in samples obtained by endosonography-guided fine-needle aspiration biopsy. Clin. Cancer Res., 10, 4444–4449.[Abstract/Free Full Text]

  103. Topaloglu, O., Hoque, M.O., Tokumaru, Y., Lee, J., Ratovitski, E., Sidransky, D. and Moon, C.S. (2004) Detection of promoter hypermethylation of multiple genes in the tumor and bronchoalveolar lavage of patients with lung cancer. Clin. Cancer Res., 10, 2284–2288.[Abstract/Free Full Text]

  104. Fukushima, N., Walter, K.M., Uek, T., Sato, N., Matsubayashi, H., Cameron, J.L., Hruban, R.H., Canto, M., Yeo, C.J. and Goggins, M. (2003) Diagnosing pancreatic cancer using methylation specific PCR analysis of pancreatic juice. Cancer Biol. Ther., 2, 78–83.[Web of Science][Medline]

  105. Honorio, S., Agathanggelou, A., Schuermann, M., Pankow, W., Viacava, P., Maher, E.R. and Latif, F. (2003) Detection of RASSF1A aberrant promoter hypermethylation in sputum from chronic smokers and ductal carcinoma in situ from breast cancer patients. Oncogene, 22, 147–150.[CrossRef][Web of Science][Medline]

  106. Chang, H.W., Chan, A., Kwong, D.L., Wei, W.I., Sham, J.S. and Yuen, A.P. (2003) Detection of hypermethylated RIZ1 gene in primary tumor, mouth, and throat rinsing fluid, nasopharyngeal swab, and peripheral blood of nasopharyngeal carcinoma patient. Clin. Cancer Res., 9, 1033–1038.[Abstract/Free Full Text]

  107. Sathyanarayana, U.G., Maruyama, R., Padar, A., Suzuki, M., Bondaruk, J., Sagalowsky, A., Minna, J.D., Frenkel, E.P., Grossman, H.B., Czerniak, B. et al. (2004) Molecular detection of noninvasive and invasive bladder tumor tissues and exfoliated cells by aberrant promoter methylation of laminin-5 encoding genes. Cancer Res., 64, 1425–1430.[Abstract/Free Full Text]

  108. Friedrich, M.G., Weisenberger, D.J., Cheng, J.C., Chandrasoma, S., Siegmund, K.D., Gonzalgo, M.L., Toma, M.I., Huland, H., Yoo, C., Tsai, Y.C. et al. (2004) Detection of methylated apoptosis-associated genes in urine sediments of bladder cancer patients. Clin. Cancer Res., 10, 7457–7465.[Abstract/Free Full Text]

  109. Battagli, C., Uzzo, R.G., Dulaimi, E., Ibanez de Caceres, I., Krassenstein, R., Al-Saleem, T., Greenberg, R.E. and Cairns, P. (2003) Promoter hypermethylation of tumor suppressor genes in urine from kidney cancer patients. Cancer Res., 63, 8695–8699.[Abstract/Free Full Text]

  110. Gonzalgo, M.L., Pavlovich, C.P., Lee, S.M. and Nelson, W.G. (2003) Prostate cancer detection by GSTP1 methylation analysis of postbiopsy urine specimens. Clin. Cancer Res., 9, 2673–2677.[Abstract/Free Full Text]

  111. Hoque, M.O., Begum, S., Topaloglu, O., Jeronimo, C., Mambo, E., Westra, W.H., Califano, J.A. and Sidransky, D. (2004) Quantitative detection of promoter hypermethylation of multiple genes in the tumor, urine, and serum DNA of patients with renal cancer. Cancer Res., 64, 5511–5517.[Abstract/Free Full Text]

  112. Ibanez de Caceres, I., Battagli, C., Esteller, M., Herman, J.G., Dulaimi, E., Edelson, M.I., Bergman, C., Ehya, H., Eisenberg, B.L. and Cairns, P. (2004) Tumor cell-specific BRCA1 and RASSF1A hypermethylation in serum, plasma, and peritoneal fluid from ovarian cancer patients. Cancer Res., 64, 6476–6481.[Abstract/Free Full Text]

  113. Muller, H.M., Millinger, S., Fiegl, H., Goebel, G., Ivarsson, L., Widschwendter, A., Muller-Holzner, E., Marth, C. and Widschwendter, M. (2004) Analysis of methylated genes in peritoneal fluids of ovarian cancer patients: a new prognostic tool. Clin. Chem., 50, 2171–2173.[Free Full Text]

  114. Widschwendter, A., Gattringer, C., Ivarsson, L., Fiegl, H., Schneitter, A., Ramoni, A., Muller, H.M., Wiedemair, A., Jerabek, S., Muller-Holzner, E. et al. (2004) Analysis of aberrant DNA methylation and human papillomavirus DNA in cervicovaginal specimens to detect invasive cervical cancer and its precursors. Clin. Cancer Res., 10, 3396–3400.[Abstract/Free Full Text]

  115. Fiegl, H., Gattringer, C., Widschwendter, A., Schneitter, A., Ramoni, A., Sarlay, D., Gaugg, I., Goebel, G., Muller, H.M., Mueller-Holzner, E. et al. (2004) Methylated DNA collected by tampons—a new tool to detect endometrial cancer. Cancer Epidemiol. Biomarkers Prev., 13, 882–888.[Abstract/Free Full Text]

  116. Lamy, A., Sesboue, R., Bourguignon, J., Dautreaux, B., Metayer, J., Frebourg, T. and Thiberville, L. (2002) Aberrant methylation of the CDKN2a/p16INK4a gene promoter region in preinvasive bronchial lesions: a prospective study in high-risk patients without invasive cancer. Int. J. Cancer, 100, 189–193.[CrossRef][Web of Science][Medline]

  117. Holst, C.R., Nuovo, G.J., Esteller, M., Chew, K., Baylin, S.B., Herman, J.G. and Tlsty, T.D. (2003) Methylation of p16(INK4a) promoters occurs in vivo in histologically normal human mammary epithelia. Cancer Res., 63, 1596–1601.[Abstract/Free Full Text]

  118. Simpson, D.J., McNicol, A.M., Murray, D.C., Bahar, A., Turner, H.E., Wass, J.A., Esiri, M.M., Clayton, R.N. and Farrell, W.E. (2004) Molecular pathology shows p16 methylation in nonadenomatous pituitaries from patients with Cushing's disease. Clin. Cancer Res., 10, 1780–1788.[Abstract/Free Full Text]

  119. Eads, C.A., Lord, R.V., Kurumboor, S.K., Wickramasinghe, K., Skinner, M.L., Long, T.I., Peters, J.H., DeMeester, T.R., Danenberg, K.D., Danenberg, P.V. et al. (2000) Fields of aberrant CpG island hypermethylation in Barrett's esophagus and associated adenocarcinoma. Cancer Res., 60, 5021–5026.[Abstract/Free Full Text]

  120. Eads, C.A., Lord, R.V., Wickramasinghe, K., Long, T.I., Kurumboor, S.K., Bernstein, L., Peters, J.H., DeMeester, S.R., DeMeester, T.R., Skinner, K.A. et al. (2001) Epigenetic patterns in the progression of esophageal adenocarcinoma. Cancer Res., 61, 3410–3418.[Abstract/Free Full Text]

  121. Kang, G.H., Lee, H.J., Hwang, K.S., Lee, S., Kim, J.H. and Kim, J.S. (2003) Aberrant CpG island hypermethylation of chronic gastritis, in relation to aging, gender, intestinal metaplasia, and chronic inflammation. Am. J. Pathol., 163, 1551–1556.[Abstract/Free Full Text]

  122. Lee, J.H., Park, S.J., Abraham, S.C., Seo, J.S., Nam, J.H., Choi, C., Juhng, S.W., Rashid, A., Hamilton, S.R. and Wu, T.T. (2004) Frequent CpG island methylation in precursor lesions and early gastric adenocarcinomas. Oncogene, 23, 4646–4654.[CrossRef][Web of Science][Medline]

  123. Sun, Y., Deng, D., You, W.C., Bai, H., Zhang, L., Zhou, J., Shen, L., Ma, J.L., Xie, Y.Q. and Li, J.Y. (2004) Methylation of p16 CpG islands associated with malignant transformation of gastric dysplasia in a population-based study. Clin. Cancer Res., 10, 5087–5093.[Abstract/Free Full Text]

  124. Jeronimo, C., Usadel, H., Henrique, R., Oliveira, J., Lopes, C., Nelson, W.G. and Sidransky, D. (2001) Quantitation of GSTP1 methylation in non-neoplastic prostatic tissue and organ-confined prostate adenocarcinoma. J. Natl Cancer Inst., 93, 1747–1752.[Abstract/Free Full Text]

  125. Brooks, J.D., Weinstein, M., Lin, X., Sun, Y., Pin, S.S., Bova, G.S., Epstein, J.I., Isaacs, W.B. and Nelson, W.G. (1998) CG island methylation changes near the GSTP1 gene in prostatic intraepithelial neoplasia. Cancer Epidemiol. Biomarkers Prev., 7, 531–536.[Abstract/Free Full Text]

  126. Takahashi, T., Shivapurkar, N., Riquelme, E., Shigematsu, H., Reddy, J., Suzuki, M., Miyajima, K., Zhou, X., Bekele, B.N., Gazdar, A.F. et al. (2004) Aberrant promoter hypermethylation of multiple genes in gallbladder carcinoma and chronic cholecystitis. Clin. Cancer Res., 10, 6126–6133.[Abstract/Free Full Text]

  127. Issa, J.P., Ahuja, N., Toyota, M., Bronner, M.P. and Brentnall, T.A. (2001) Accelerated age-related CpG island methylation in ulcerative colitis. Cancer Res., 61, 3573–3577.[Abstract/Free Full Text]

  128. Guo, M., House, M.G., Hooker, C., Han, Y., Heath, E., Gabrielson, E., Yang, S.C., Baylin, S.B., Herman, J.G. and Brock, M.V. (2004) Promoter hypermethylation of resected bronchial margins: a field defect of changes? Clin. Cancer Res., 10, 5131–5136.[Abstract/Free Full Text]

  129. Anttila, S., Hakkola, J., Tuominen, P., Elovaara, E., Husgafvel-Pursiainen, K., Karjalainen, A., Hirvonen, A. and Nurminen, T. (2003) Methylation of cytochrome P4501A1 promoter in the lung is associated with tobacco smoking. Cancer Res., 63, 8623–8628.[Abstract/Free Full Text]

  130. Yuasa, Y., Nagasaki, H., Akiyama, Y., Sakai, H., Nakajima, T., Ohkura, Y., Takizawa, T., Koike, M., Tani, M., Iwai, T. et al. (2005) Relationship between CDX2 gene methylation and dietary factors in gastric cancer patients. Carcinogenesis, 26, 193–200.[Abstract/Free Full Text]

  131. Kopelovich, L., Crowell, J.A. and Fay, J.R. (2003) The epigenome as a target for cancer chemoprevention. J. Natl Cancer Inst., 95, 1747–1757.[Abstract/Free Full Text]

  132. Markl, I.D., Cheng, J., Liang, G., Shibata, D., Laird, P.W. and Jones, P.A. (2001) Global and gene-specific epigenetic patterns in human bladder cancer genomes are relatively stable in vivo and in vitro over time. Cancer Res., 61, 5875–5884.[Abstract/Free Full Text]

  133. Gerasimova, T.I. and Corces, V.G. (2001) Chromatin insulators and boundaries: effects on transcription and nuclear organization. Annu. Rev. Genet., 35, 193–208.[CrossRef][Web of Science][Medline]

  134. Mutskov, V.J., Farrell, C.M., Wade, P.A., Wolffe, A.P. and Felsenfeld, G. (2002) The barrier function of an insulator couples high histone acetylation levels with specific protection of promoter DNA from methylation. Genes Dev., 16, 1540–1554.[Abstract/Free Full Text]

  135. Yu, W., Ginjala, V., Pant, V., Chernukhin, I., Whitehead, J., Docquier, F., Farrar, D., Tavoosidana, G., Mukhopadhyay, R., Kanduri, C. et al. (2004) Poly(ADP-ribosyl)ation regulates CTCF-dependent chromatin insulation. Nat. Genet., 36, 1105–1110.[CrossRef][Web of Science][Medline]

  136. Gilbert, N., Boyle, S., Fiegler, H., Woodfine, K., Carter, N.P. and Bickmore, W.A. (2004) Chromatin architecture of the human genome: gene-rich domains are enriched in open chromatin fibers. Cell, 118, 555–566.[CrossRef][Web of Science][Medline]

  137. Oberley, M.J. and Farnham, P.J. (2003) Probing chromatin immunoprecipitates with CpG-island microarrays to identify genomic sites occupied by DNA-binding proteins. Methods Enzymol., 371, 577–596.[Web of Science][Medline]

  138. Watanabe, T., Yoshimura, A., Mishima, Y., Endo, Y., Shiroishi, T., Koide, T., Sasaki, H., Asakura, H. and Kominami, R. (2000) Differential chromatin packaging of genomic imprinted regions between expressed and non-expressed alleles. Hum. Mol. Genet., 9, 3029–3035.[Abstract/Free Full Text]

  139. Vertino, P.M., Yen, R.W., Gao, J. and Baylin, S.B. (1996) De novo methylation of CpG island sequences in human fibroblasts overexpressing DNA (cytosine-5-)-methyltransferase. Mol. Cell. Biol., 16, 4555–4565.[Abstract]

  140. Ordway, J.M., Williams, K. and Curran, T. (2004) Transcription repression in oncogenic transformation: common targets of epigenetic repression in cells transformed by Fos, Ras or Dnmt1. Oncogene, 23, 3737–3748.[CrossRef][Web of Science][Medline]

  141. Feltus, F.A., Lee, E.K., Costello, J.F., Plass, C. and Vertino, P.M. (2003) Predicting aberrant CpG island methylation. Proc. Natl Acad. Sci. USA, 100, 12253–12258.[Abstract/Free Full Text]

  142. Okano, M., Bell, D.W., Haber, D.A. and Li, E. (1999) DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell, 99, 247–257.[CrossRef][Web of Science][Medline]

  143. Rhee, I., Bachman, K.E., Park, B.H., Jair, K.W., Yen, R.W., Schuebel, K.E., Cui, H., Feinberg, A.P., Lengauer, C., Kinzler, K.W. et al. (2002) DNMT1 and DNMT3b cooperate to silence genes in human cancer cells. Nature, 416, 552–556.[CrossRef][Web of Science][Medline]

  144. Paz, M.F., Wei, S., Cigudosa, J.C., Rodriguez-Perales, S., Peinado, M.A., Huang, T.H. and Esteller, M. (2003) Genetic unmasking of epigenetically silenced tumor suppressor genes in colon cancer cells deficient in DNA methyltransferases. Hum. Mol. Genet., 12, 2209–2219.[Abstract/Free Full Text]

  145. Robert, M.F., Morin, S., Beaulieu, N., Gauthier, F., Chute, I.C., Barsalou, A. and MacLeod, A.R. (2003) DNMT1 is required to maintain CpG methylation and aberrant gene silencing in human cancer cells. Nat. Genet., 33, 61–65.[CrossRef][Web of Science][Medline]

  146. Yan, Q., Huang, J., Fan, T., Zhu, H. and Muegge, K. (2003) Lsh, a modulator of CpG methylation, is crucial for normal histone methylation. EMBO J., 22, 5154–5162.[CrossRef][Web of Science][Medline]

  147. Fan, T., Hagan, J.P., Kozlov, S.V., Stewart, C.L. and Muegge, K. (2005) Lsh controls silencing of the imprinted Cdkn1c gene. Development, 12, 12.

  148. Huang, J., Fan, T., Yan, Q., Zhu, H., Fox, S., Issaq, H.J., Best, L., Gangi, L., Munroe, D. and Muegge, K. (2004) Lsh, an epigenetic guardian of repetitive elements. Nucleic Acids Res., 32, 5019–5028.[Abstract/Free Full Text]

  149. Morris, K.V., Chan, S.W., Jacobsen, S.E. and Looney, D.J. (2004) Small interfering RNA-induced transcriptional gene silencing in human cells. Science, 305, 1289–1292.[Abstract/Free Full Text]

  150. Kawasaki, H. and Taira, K. (2004) Induction of DNA methylation and gene silencing by short interfering RNAs in human cells. Nature, 431, 211–217.[CrossRef][Web of Science][Medline]

  151. Toyota, M., Ahuja, N., Ohe-Toyota, M., Herman, J.G., Baylin, S.B. and Issa, J.P. (1999) CpG island methylator phenotype in colorectal cancer. Proc. Natl Acad. Sci. USA, 96, 8681–8686.

  152. Issa, J.P. (2004) CpG island methylator phenotype in cancer. Nat. Rev. Cancer, 4, 988–993.[CrossRef][Web of Science][Medline]

  153. Yamashita, K., Dai, T., Dai, Y., Yamamoto, F. and Perucho, M. (2003) Genetics supersedes epigenetics in colon cancer phenotype. Cancer Cell, 4, 121–131.[CrossRef][Web of Science][Medline]

  154. Van Rijnsoever, M., Elsaleh, H., Joseph, D., McCaul, K. and Iacopetta, B. (2003) CpG island methylator phenotype is an independent predictor of survival benefit from 5-fluorouracil in stage III colorectal cancer. Clin. Cancer Res., 9, 2898–2903.[Abstract/Free Full Text]

  155. Toyota, M., Ohe-Toyota, M., Ahuja, N. and Issa, J.P. (2000) Distinct genetic profiles in colorectal tumors with or without the CpG island methylator phenotype. Proc. Natl Acad. Sci. USA, 97, 710–715.[Abstract/Free Full Text]

  156. Toyota, M., Itoh, F. and Imai, K. (2000) DNA methylation and gastrointestinal malignancies: functional consequences and clinical implications. J. Gastroenterol., 35, 727–734.[CrossRef][Web of Science][Medline]

  157. Frazier, M.L., Xi, L., Zong, J., Viscofsky, N., Rashid, A., Wu, E.F., Lynch, P.M., Amos, C.I. and Issa, J.P. (2003) Association of the CpG island methylator phenotype with family history of cancer in patients with colorectal cancer. Cancer Res., 63, 4805–4808.[Abstract/Free Full Text]

  158. Ward, R.L., Williams, R., Law, M. and Hawkins, N.J. (2004) The CpG island methylator phenotype is not associated with a personal or family history of cancer. Cancer Res., 64, 7618–7621.[Abstract/Free Full Text]

  159. Cui, H., Horon, I.L., Ohlsson, R., Hamilton, S.R. and Feinberg, A.P. (1998) Loss of imprinting in normal tissue of colorectal cancer patients with microsatellite instability. Nat. Med., 4, 1276–1280.[CrossRef][Web of Science][Medline]

  160. Cui, H., Cruz-Correa, M., Giardiello, F.M., Hutcheon, D.F., Kafonek, D.R., Brandenburg, S., Wu, Y., He, X., Powe, N.R. and Feinberg, A.P. (2003) Loss of IGF2 imprinting: a potential marker of colorectal cancer risk. Science, 299, 1753–1755.[Abstract/Free Full Text]

  161. Cunningham, J.M., Christensen, E.R., Tester, D.J., Kim, C.Y., Roche, P.C., Burgart, L.J. and Thibodeau, S.N. (1998) Hypermethylation of the hMLH1 promoter in colon cancer with microsatellite instability. Cancer Res., 58, 3455–3460.[Abstract/Free Full Text]

  162. Esteller, M., Levine, R., Baylin, S.B., Ellenson, L.H. and Herman, J.G. (1998) MLH1 promoter hypermethylation is associated with the microsatellite instability phenotype in sporadic endometrial carcinomas. Oncogene, 17, 2413–2417.[CrossRef][Web of Science][Medline]

  163. Herman, J.G., Umar, A., Polyak, K., Graff, J.R., Ahuja, N., Issa, J.P., Markowitz, S., Willson, J.K., Hamilton, S.R., Kinzler, K.W. et al. (1998) Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. Proc. Natl Acad. Sci. USA, 95, 6870–6875.[Abstract/Free Full Text]

  164. Veigl, M.L., Kasturi, L., Olechnowicz, J., Ma, A.H., Lutterbaugh, J.D., Periyasamy, S., Li, G.M., Drummond, J., Modrich, P.L., Sedwick, W.D. et al. (1998) Biallelic inactivation of hMLH1 by epigenetic gene silencing, a novel mechanism causing human MSI cancers. Proc. Natl Acad. Sci. USA, 95, 8698–8702.[Abstract/Free Full Text]

  165. Nakagawa, H., Nuovo, G.J., Zervos, E.E., Martin, E.W., Jr, Salovaara, R., Aaltonen, L.A. and de la Chapelle, A. (2001) Age-related hypermethylation of the 5' region of MLH1 in normal colonic mucosa is associated with microsatellite-unstable colorectal cancer development. Cancer Res., 61, 6991–6995.[Abstract/Free Full Text]

  166. Gazzoli, I., Loda, M., Garber, J., Syngal, S. and Kolodner, R.D. (2002) A hereditary nonpolyposis colorectal carcinoma case associated with hypermethylation of the MLH1 gene in normal tissue and loss of heterozygosity of the unmethylated allele in the resulting microsatellite instability-high tumor. Cancer Res., 62, 3925–3928.[Abstract/Free Full Text]

  167. Suter, C.M., Martin, D.I. and Ward, R.L. (2004) Germline epimutation of MLH1 in individuals with multiple cancers. Nat. Genet., 36, 497–501.[CrossRef][Web of Science][Medline]

  168. Miyakura, Y., Sugano, K., Akasu, T., Yoshida, T., Maekawa, M., Saitoh, S., Sasaki, H., Nomizu, T., Konishi, F., Fujita, S. et al. (2004) Extensive but hemiallelic methylation of the hMLH1 promoter region in early-onset sporadic colon cancers with microsatellite instability. Clin. Gastroenterol. Hepatol., 2, 147–156.[CrossRef][Medline]

  169. Rakyan, V.K., Chong, S., Champ, M.E., Cuthbert, P.C., Morgan, H.D., Luu, K.V. and Whitelaw, E. (2003) Transgenerational inheritance of epigenetic states at the murine Axin(Fu) allele occurs after maternal and paternal transmission. Proc. Natl Acad. Sci. USA, 100, 2538–2543.[Abstract/Free Full Text]

  170. Morgan, H.D., Sutherland, H.G., Martin, D.I. and Whitelaw, E. (1999) Epigenetic inheritance at the agouti locus in the mouse. Nat. Genet., 23, 314–318.[CrossRef][Web of Science][Medline]

  171. Herman, H., Lu, M., Anggraini, M., Sikora, A., Chang, Y., Yoon, B.J. and Soloway, P.D. (2003) Trans allele methylation and paramutation-like effects in mice. Nat. Genet., 34, 199–202.[CrossRef][Web of Science][Medline]

  172. Laird, P.W., Jackson-Grusby, L., Fazeli, A., Dickinson, S.L., Jung, W.E., Li, E., Weinberg, R.A. and Jaenisch, R. (1995) Suppression of intestinal neoplasia by DNA hypomethylation. Cell, 81, 197–205.[CrossRef][Web of Science][Medline]

  173. Cormier, R.T. and Dove, W.F. (2000) Dnmt1N/+ reduces the net growth rate and multiplicity of intestinal adenomas in C57BL/6-multiple intestinal neoplasia (Min)/+ mice independently of p53 but demonstrates strong synergy with the modifier of Min 1(AKR) resistance allele. Cancer Res., 60, 3965–3970.[Abstract/Free Full Text]

  174. Eads, C.A., Nickel, A.E. and Laird, P.W. (2002) Complete genetic suppression of polyp formation and reduction of CpG-island hypermethylation in Apc(Min/+) Dnmt1-hypomorphic mice. Cancer Res., 62, 1296–1299.[Abstract/Free Full Text]

  175. Sansom, O.J., Berger, J., Bishop, S.M., Hendrich, B., Bird, A. and Clarke, A.R. (2003) Deficiency of Mbd2 suppresses intestinal tumorigenesis. Nat. Genet., 34, 145–147.[CrossRef][Web of Science][Medline]

  176. Baylin, S. and Bestor, T.H. (2002) Altered methylation patterns in cancer cell genomes: cause or consequence? Cancer Cell, 1, 299–305.[CrossRef][Web of Science][Medline]

  177. Trinh, B.N., Long, T.I., Nickel, A.E., Shibata, D. and Laird, P.W. (2002) DNA methyltransferase deficiency modifies cancer susceptibility in mice lacking DNA mismatch repair. Mol. Cell. Biol., 22, 2906–2917.[Abstract/Free Full Text]

  178. Gaudet, F., Hodgson, J.G., Eden, A., Jackson-Grusby, L., Dausman, J., Gray, J.W., Leonhardt, H. and Jaenisch, R. (2003) Induction of tumors in mice by genomic hypomethylation. Science, 300, 489–492.[Abstract/Free Full Text]

  179. Eden, A., Gaudet, F., Waghmare, A. and Jaenisch, R. (2003) Chromosomal instability and tumors promoted by DNA hypomethylation. Science, 300, 455.[Free Full Text]

  180. Chen, R.Z., Pettersson, U., Beard, C., Jackson-Grusby, L. and Jaenisch, R. (1998) DNA hypomethylation leads to elevated mutation rates. Nature, 395, 89–93.[CrossRef][Medline]

  181. Tsien, F., Fiala, E.S., Youn, B., Long, T.I., Laird, P.W., Weissbecker, K. and Ehrlich, M. (2002) Prolonged culture of normal chorionic villus cells yields ICF syndrome-like chromatin decondensation and rearrangements. Cytogenet. Genome Res., 98, 13–21.[CrossRef][Web of Science][Medline]

  182. Xu, G.L., Bestor, T.H., Bourc'his, D., Hsieh, C.L., Tommerup, N., Bugge, M., Hulten, M., Qu, X., Russo, J.J. and Viegas-Pequignot, E. (1999) Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene. Nature, 402, 187–191.[CrossRef][Medline]

  183. Hansen, R.S., Wijmenga, C., Luo, P., Stanek, A.M., Canfield, T.K., Weemaes, C.M. and Gartler, S.M. (1999) The DNMT3B DNA methyltransferase gene is mutated in the ICF immunodeficiency syndrome. Proc. Natl Acad. Sci. USA, 96, 14412–14417.[Abstract/Free Full Text]

  184. Chan, M.F., van Amerongen, R., Nijjar, T., Cuppen, E., Jones, P.A. and Laird, P.W. (2001) Reduced rates of gene loss, gene silencing, and gene mutation in dnmt1- deficient embryonic stem cells. Mol. Cell. Biol., 21, 7587–7600.[Abstract/Free Full Text]

  185. Guo, G., Wang, W. and Bradley, A. (2004) Mismatch repair genes identified using genetic screens in Blm-deficient embryonic stem cells. Nature, 429, 891–895.[CrossRef][Medline]

  186. Kim, M., Trinh, B.N., Long, T.I., Oghamian, S. and Laird, P.W. (2004) Dnmt1 deficiency leads to enhanced microsatellite instability in mouse embryonic stem cells. Nucleic Acids Res., 32, 5742–5749.[Abstract/Free Full Text]

  187. Wang, K.Y. and James Shen, C.K. (2004) DNA methyltransferase Dnmt1 and mismatch repair. Oncogene, 23, 7898–7902.[CrossRef][Web of Science][Medline]

  188. Gorbunova, V., Seluanov, A., Mittelman, D. and Wilson, J.H. (2004) Genome-wide demethylation destabilizes CTG. CAG trinucleotide repeats in mammalian cells. Hum. Mol. Genet., 13, 2979–2989.[Abstract/Free Full Text]

  189. Kornblith, A.B., Herndon, J.E., II, Silverman, L.R., Demakos, E.P., Odchimar-Reissig, R., Holland, J.F., Powell, B.L., DeCastro, C., Ellerton, J., Larson, R.A. et al. (2002) Impact of azacytidine on the quality of life of patients with myelodysplastic syndrome treated in a randomized phase III trial: a Cancer and Leukemia Group B study. J. Clin. Oncol., 20, 2441–2452.[Abstract/Free Full Text]

  190. El-Osta, A., Lubbert, M., Wijermans, P.W., Licht, T. and Jones, P.A. (2003) On the use of DNA methylation inhibitors and the reversal of transcriptional silencing. Blood, 101, 1656–1657.[Free Full Text]

  191. Lübbert, M., Haak, H.L., Kunzman, R., Danzer-Driessen, S., Verhoef, G., Mertelsmann, R. and Wijermans, P. (1997) Cytogenic response to low-dose 5-aza-2'-deoxycytidine (DAC) in poor-risk myelodysplastic syndromes (MDS)—phase II study results. Blood, 90 (Suppl. 1), 582a.

  192. Kantarjian, H.M., O'Brien, S., Cortes, J., Giles, F.J., Faderl, S., Issa, J.P., Garcia-Manero, G., Rios, M.B., Shan, J., Andreeff, M. et al. (2003) Results of decitabine (5-aza-2'deoxycytidine) therapy in 130 patients with chronic myelogenous leukemia. Cancer, 98, 522–528.[CrossRef][Web of Science][Medline]

  193. Aparicio, A., Eads, C.A., Leong, L.A., Laird, P.W., Newman, E.M., Synold, T.W., Baker, S.D., Zhao, M. and Weber, J.S. (2003) Phase I trial of continuous infusion 5-aza-2'-deoxycytidine. Cancer Chemother. Pharmacol., 51, 231–239.[Web of Science][Medline]

  194. Williamson, S.K., Crowley, J.J., Livingston, R.B., Panella, T.J. and Goodwin, J.W. (1995) Phase II trial and cost analysis of fazarabine in advanced non-small cell carcinoma of the lung: a Southwest Oncology Group study. Invest. New Drugs, 13, 67–71.[Web of Science][Medline]

  195. Kees, U.R. and Avramis, V.I. (1995) Biochemical pharmacology and DNA methylation studies of arabinosyl 5-azacytidine and 5,6-dihydro-5-azacytidine in two human leukemia cell lines PER-145 and PER-163. Anticancer Drugs, 6, 303–310.[Medline]

  196. Samuels, B.L., Herndon, J.E., II, Harmon, D.C., Carey, R., Aisner, J., Corson, J.M., Suzuki, Y., Green, M.R. and Vogelzang, N.J. (1998) Dihydro-5-azacytidine and cisplatin in the treatment of malignant mesothelioma: a phase II study by the Cancer and Leukemia Group B. Cancer, 82, 1578–1584.

  197. Keith, B., Xu, Y. and Grem, J.L. (2003) Measurement of the anti-cancer agent gemcitabine in human plasma by high-performance liquid chromatography. J. Chromatogr. B. Analyt. Technol. Biomed. Life Sci., 785, 65–72.[Web of Science][Medline]

  198. Flynn, J., Fang, J.Y., Mikovits, J.A. and Reich, N.O. (2003) A potent cell-active allosteric inhibitor of murine DNA cytosine C5 methyltransferase. J. Biol. Chem., 278, 8238–8243.[Abstract/Free Full Text]

  199. Fang, M.Z., Wang, Y., Ai, N., Hou, Z., Sun, Y., Lu, H., Welsh, W. and Yang, C.S. (2003) Tea polyphenol (–)-epigallocatechin-3-gallate inhibits DNA methyltransferase and reactivates methylation-silenced genes in cancer cell lines. Cancer Res., 63, 7563–7570.[Abstract/Free Full Text]

  200. Segura-Pacheco, B., Trejo-Becerril, C., Perez-Cardenas, E., Taja-Chayeb, L., Mariscal, I., Chavez, A., Acuna, C., Salazar, A.M., Lizano, M. and Duenas-Gonzalez, A. (2003) Reactivation of tumor suppressor genes by the cardiovascular drugs hydralazine and procainamide and their potential use in cancer therapy. Clin. Cancer Res., 9, 1596–1603.[Abstract/Free Full Text]

  201. Stewart, D.J., Donehower, R.C., Eisenhauer, E.A., Wainman, N., Shah, A.K., Bonfils, C., MacLeod, A.R., Besterman, J.M. and Reid, G.K. (2003) A phase I pharmacokinetic and pharmacodynamic study of the DNA methyltransferase 1 inhibitor MG98 administered twice weekly. Ann. Oncol., 14, 766–774.[Abstract/Free Full Text]

  202. Lin, X., Asgari, K., Putzi, M.J., Gage, W.R., Yu, X., Cornblatt, B.S., Kumar, A., Piantadosi, S., DeWeese, T.L., De Marzo, A.M. et al. (2001) Reversal of GSTP1 CpG island hypermethylation and reactivation of pi-class glutathione S-transferase (GSTP1) expression in human prostate cancer cells by treatment with procainamide. Cancer Res., 61, 8611–8616.[Abstract/Free Full Text]

  203. Villar-Garea, A., Fraga, M.F., Espada, J. and Esteller, M. (2003) Procaine is a DNA-demethylating agent with growth-inhibitory effects in human cancer cells. Cancer Res., 63, 4984–4989.[Abstract/Free Full Text]

  204. Suzuki, M., Sunaga, N., Shames, D.S., Toyooka, S., Gazdar, A.F. and Minna, J.D. (2004) RNA interference-mediated knockdown of DNA methyltransferase 1 leads to promoter demethylation and gene re-expression in human lung and breast cancer cells. Cancer Res., 64, 3137–3143.[Abstract/Free Full Text]

  205. Ting, A.H., Jair, K.W., Suzuki, H., Yen, R.W., Baylin, S.B. and Schuebel, K.E. (2004) CpG island hypermethylation is maintained in human colorectal cancer cells after RNAi-mediated depletion of DNMT1. Nat. Genet., 36, 582–584.[CrossRef][Web of Science][Medline]

  206. Leu, Y.W., Rahmatpanah, F., Shi, H., Wei, S.H., Liu, J.C., Yan, P.S. and Huang, T.H. (2003) Double RNA interference of DNMT3b and DNMT1 enhances DNA demethylation and gene reactivation. Cancer Res., 63, 6110–6115.[Abstract/Free Full Text]

  207. Kwon, S.H., Ahn, S.H., Kim, Y.K., Bae, G.U., Yoon, J.W., Hong, S., Lee, H.Y., Lee, Y.W., Lee, H.W. and Han, J.W. (2002) Apicidin, a histone deacetylase inhibitor, induces apoptosis and Fas/Fas ligand expression in human acute promyelocytic leukemia cells. J. Biol. Chem., 277, 2073–2080.[Abstract/Free Full Text]

  208. Ammerpohl, O., Thormeyer, D., Khan, Z., Appelskog, I.B., Gojkovic, Z., Almqvist, P.M. and Ekstrom, T.J. (2004) HDACi phenylbutyrate increases bystander killing of HSV-tk transfected glioma cells. Biochem. Biophys. Res. Commun., 324, 8–14.[CrossRef][Web of Science][Medline]

  209. Takai, N., Desmond, J.C., Kumagai, T., Gui, D., Said, J.W., Whittaker, S., Miyakawa, I. and Koeffler, H.P. (2004) Histone deacetylase inhibitors have a profound antigrowth activity in endometrial cancer cells. Clin. Cancer Res., 10, 1141–1149.[Abstract/Free Full Text]

  210. Reid, T., Valone, F., Lipera, W., Irwin, D., Paroly, W., Natale, R., Sreedharan, S., Keer, H., Lum, B., Scappaticci, F. et al. (2004) Phase II trial of the histone deacetylase inhibitor pivaloyloxymethyl butyrate (Pivanex, AN-9) in advanced non-small cell lung cancer. Lung Cancer, 45, 381–386.[CrossRef][Web of Science][Medline]

  211. Glick, R.D., Swendeman, S.L., Coffey, D.C., Rifkind, R.A., Marks, P.A., Richon, V.M. and La Quaglia, M.P. (1999) Hybrid polar histone deacetylase inhibitor induces apoptosis and CD95/CD95 ligand expression in human neuroblastoma. Cancer Res., 59, 4392–4399.[Abstract/Free Full Text]

  212. Coffey, D.C., Kutko, M.C., Glick, R.D., Butler, L.M., Heller, G., Rifkind, R.A., Marks, P.A., Richon, V.M. and La Quaglia, M.P. (2001) The histone deacetylase inhibitor, CBHA, inhibits growth of human neuroblastoma xenografts in vivo, alone and synergistically with all-trans retinoic acid. Cancer Res., 61, 3591–3594.[Abstract/Free Full Text]

  213. Komatsu, Y., Tomizaki, K.Y., Tsukamoto, M., Kato, T., Nishino, N., Sato, S., Yamori, T., Tsuruo, T., Furumai, R., Yoshida, M. et al. (2001) Cyclic hydroxamic-acid-containing peptide 31, a potent synthetic histone deacetylase inhibitor with antitumor activity. Cancer Res., 61, 4459–4466.[Abstract/Free Full Text]

  214. Kwon, H.J., Owa, T., Hassig, C.A., Shimada, J. and Schreiber, S.L. (1998) Depudecin induces morphological reversion of transformed fibroblasts via the inhibition of histone deacetylase. Proc. Natl Acad. Sci. USA, 95, 3356–3361.[Abstract/Free Full Text]

  215. Khan, S.B., Maududi, T., Barton, K., Ayers, J. and Alkan, S. (2004) Analysis of histone deacetylase inhibitor, depsipeptide (FR901228), effect on multiple myeloma. Br. J. Haematol., 125, 156–161.[CrossRef][Web of Science][Medline]

  216. Lucas, D.M., Davis, M.E., Parthun, M.R., Mone, A.P., Kitada, S., Cunningham, K.D., Flax, E.L., Wickham, J., Reed, J.C., Byrd, J.C. et al. (2004) The histone deacetylase inhibitor MS-275 induces caspase-dependent apoptosis in B-cell chronic lymphocytic leukemia cells. Leukemia, 18, 1207–1214.[CrossRef][Web of Science][Medline]

  217. Remiszewski, S.W. (2003) The discovery of NVP-LAQ824: from concept to clinic. Curr. Med. Chem., 10, 2393–2402.[CrossRef][Web of Science][Medline]

  218. Kim, Y.B., Lee, K.H., Sugita, K., Yoshida, M. and Horinouchi, S. (1999) Oxamflatin is a novel antitumor compound that inhibits mammalian histone deacetylase. Oncogene, 18, 2461–2470.[CrossRef][Web of Science][Medline]

  219. Garber, K. (2004) Purchase of Aton spotlights HDAC inhibitors. Nat. Biotechnol., 22, 364–365.[CrossRef][Web of Science][Medline]

  220. Plumb, J.A., Finn, P.W., Williams, R.J., Bandara, M.J., Romero, M.R., Watkins, C.J., La Thangue, N.B. and Brown, R. (2003) Pharmacodynamic response and inhibition of growth of human tumor xenografts by the novel histone deacetylase inhibitor PXD101. Mol. Cancer Ther., 2, 721–728.[Abstract/Free Full Text]

  221. Butler, L.M., Webb, Y., Agus, D.B., Higgins, B., Tolentino, T.R., Kutko, M.C., LaQuaglia, M.P., Drobnjak, M., Cordon-Cardo, C., Scher, H.I. et al. (2001) Inhibition of transformed cell growth and induction of cellular differentiation by pyroxamide, an inhibitor of histone deacetylase. Clin. Cancer Res., 7, 962–970.[Abstract/Free Full Text]

  222. Nebbioso, A., Clarke, N., Voltz, E., Germain, E., Ambrosino, C., Bontempo, P., Alvarez, R., Schiavone, E.M., Ferrara, F., Bresciani, F. et al. (2005) Tumor-selective action of HDAC inhibitors involves TRAIL induction in acute myeloid leukemia cells. Nat. Med., 11, 77–84.[CrossRef][Web of Science][Medline]

  223. Zhang, X.D., Gillespie, S.K., Borrow, J.M. and Hersey, P. (2004) The histone deacetylase inhibitor suberic bishydroxamate regulates the expression of multiple apoptotic mediators and induces mitochondria-dependent apoptosis of melanoma cells. Mol. Cancer Ther., 3, 425–435.[Abstract/Free Full Text]

  224. Kelly, W.K., Richon, V.M., O'Connor, O., Curley, T., MacGregor-Curtelli, B., Tong, W., Klang, M., Schwartz, L., Richardson, S., Rosa, E. et al. (2003) Phase I clinical trial of histone deacetylase inhibitor: suberoylanilide hydroxamic acid administered intravenously. Clin. Cancer Res., 9, 3578–3588.[Abstract/Free Full Text]

  225. Vanhaecke, T., Papeleu, P., Elaut, G. and Rogiers, V. (2004) Trichostatin A-like hydroxamate histone deacetylase inhibitors as therapeutic agents: toxicological point of view. Curr. Med. Chem., 11, 1629–1643.[Web of Science][Medline]

  226. Kijima, M., Yoshida, M., Sugita, K., Horinouchi, S. and Beppu, T. (1993) Trapoxin, an antitumor cyclic tetrapeptide, is an irreversible inhibitor of mammalian histone deacetylase. J. Biol. Chem., 268, 22429–22435.[Abstract/Free Full Text]

  227. Kramer, O.H., Zhu, P., Ostendorff, H.P., Golebiewski, M., Tiefenbach, J., Peters, M.A., Brill, B., Groner, B., Bach, I., Heinzel, T. et al. (2003) The histone deacetylase inhibitor valproic acid selectively induces proteasomal degradation of HDAC2. EMBO J., 22, 3411–3420.[CrossRef][Web of Science][Medline]


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 BloodHome page
J. Hiraga, A. Tomita, T. Sugimoto, K. Shimada, M. Ito, S. Nakamura, H. Kiyoi, T. Kinoshita, and T. Naoe
Down-regulation of CD20 expression in B-cell lymphoma cells after treatment with rituximab-containing combination chemotherapies: its prevalence and clinical significance
Blood, May 14, 2009; 113(20): 4885 - 4893.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
J. I. Martin-Subero, M. Kreuz, M. Bibikova, S. Bentink, O. Ammerpohl, E. Wickham-Garcia, M. Rosolowski, J. Richter, L. Lopez-Serra, E. Ballestar, et al.
New insights into the biology and origin of mature aggressive B-cell lymphomas by combined epigenomic, genomic, and transcriptional profiling
Blood, March 12, 2009; 113(11): 2488 - 2497.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
K. Ramachandran, G. Gopisetty, E. Gordian, L. Navarro, C. Hader, I. M. Reis, W. A. Schulz, and R. Singal
Methylation-Mediated Repression of GADD45{alpha} in Prostate Cancer and Its Role as a Potential Therapeutic Target
Cancer Res., February 15, 2009; 69(4): 1527 - 1535.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Epidemiol. Biomarkers Prev.Home page
C. M. Ulrich
Folate and Cancer Prevention--Where to Next? Counterpoint
Cancer Epidemiol. Biomarkers Prev., September 1, 2008; 17(9): 2226 - 2230.
[Full Text] [PDF]

Home page
 Cancer Res.Home page
P. Kapoor-Vazirani, J. D. Kagey, D. R. Powell, and P. M. Vertino
Role of hMOF-Dependent Histone H4 Lysine 16 Acetylation in the Maintenance of TMS1/ASC Gene Activity
Cancer Res., August 15, 2008; 68(16): 6810 - 6821.
[Abstract] [Full Text] [PDF]

Home page
 Nucleic Acids ResHome page
D. J. Weisenberger, B. N. Trinh, M. Campan, S. Sharma, T. I. Long, S. Ananthnarayan, G. Liang, F. J. Esteva, G. N. Hortobagyi, F. McCormick, et al.
DNA methylation analysis by digital bisulfite genomic sequencing and digital MethyLight
Nucleic Acids Res., August 1, 2008; 36(14): 4689 - 4698.
[Abstract] [Full Text] [PDF]

Home page
 Nucleic Acids ResHome page
C. Bock, J. Walter, M. Paulsen, and T. Lengauer
Inter-individual variation of DNA methylation and its implications for large-scale epigenome mapping
Nucleic Acids Res., June 1, 2008; 36(10): e55 - e55.
[Abstract] [Full Text] [PDF]

Home page
 BioinformaticsHome page
M. Hackenberg and R. Matthiesen
Annotation-Modules: a tool for finding significant combinations of multisource annotations for gene lists
Bioinformatics, June 1, 2008; 24(11): 1386 - 1393.
[Abstract] [Full Text] [PDF]

Home page
 Mol Cancer ResHome page
P. Karpinski, D. Ramsey, Z. Grzebieniak, M. M. Sasiadek, and N. Blin
The CpG Island Methylator Phenotype Correlates with Long-Range Epigenetic Silencing in Colorectal Cancer
Mol. Cancer Res., April 1, 2008; 6(4): 585 - 591.
[Abstract] [Full Text] [PDF]

Home page
 Br Med BullHome page
A. R. Isles and L. S. Wilkinson
Epigenetics: what is it and why is it important to mental disease?
Br. Med. Bull., March 1, 2008; 85(1): 35 - 45.
[Abstract] [Full Text] [PDF]

Home page
 Nucleic Acids ResHome page
J. Rodriguez, L. Vives, M. Jorda, C. Morales, M. Munoz, E. Vendrell, and M. A. Peinado
Genome-wide tracking of unmethylated DNA Alu repeats in normal and cancer cells
Nucleic Acids Res., February 11, 2008; 36(3): 770 - 784.
[Abstract] [Full Text] [PDF]

Home page
 Nucleic Acids ResHome page
J. A. Dahl and P. Collas
{micro}ChIP--a rapid micro chromatin immunoprecipitation assay for small cell samples and biopsies
Nucleic Acids Res., February 11, 2008; 36(3): e15 - e15.
[Abstract] [Full Text] [PDF]

Home page
 Mol Cancer ResHome page
M. V. Mishra, K. S. Bisht, L. Sun, K. Muldoon-Jacobs, R. Awwad, A. Kaushal, P. Nguyen, L. Huang, J. D. Pennington, S. Markovina, et al.
DNMT1 as a Molecular Target in a Multimodality-Resistant Phenotype in Tumor Cells
Mol. Cancer Res., February 1, 2008; 6(2): 243 - 249.
[Abstract] [Full Text] [PDF]

Home page
 Circ. Res.Home page
B. Illi, C. D. Russo, C. Colussi, J. Rosati, M. Pallaoro, F. Spallotta, D. Rotili, S. Valente, G. Ragone, F. Martelli, et al.
Nitric Oxide Modulates Chromatin Folding in Human Endothelial Cells via Protein Phosphatase 2A Activation and Class II Histone Deacetylases Nuclear Shuttling
Circ. Res., January 4, 2008; 102(1): 51 - 58.
[Abstract] [Full Text] [PDF]

Home page
 J. Mol. Diagn.Home page
S. Ogino and A. Goel
Molecular Classification and Correlates in Colorectal Cancer
J. Mol. Diagn., January 1, 2008; 10(1): 13 - 27.
[Abstract] [Full Text] [PDF]

Home page
 J. Nutr.Home page
L. Fini, M. Selgrad, V. Fogliano, G. Graziani, M. Romano, E. Hotchkiss, Y. A. Daoud, E. B. De Vol, C. R. Boland, and L. Ricciardiello
Annurca Apple Polyphenols Have Potent Demethylating Activity and Can Reactivate Silenced Tumor Suppressor Genes in Colorectal Cancer Cells
J. Nutr., December 1, 2007; 137(12): 2622 - 2628.
[Abstract] [Full Text] [PDF]

Home page
 GutHome page
S. Ogino, T. Kawasaki, G. J Kirkner, Y. Suemoto, J. A Meyerhardt, and C. S Fuchs
Molecular correlates with MGMT promoter methylation and silencing support CpG island methylator phenotype-low (CIMP-low) in colorectal cancer
Gut, November 1, 2007; 56(11): 1564 - 1571.
[Abstract] [Full Text] [PDF]

Home page
 Genome ResHome page
M. R.H. Estecio, P. S. Yan, A. E.K. Ibrahim, C. S. Tellez, L. Shen, T. H.-M. Huang, and J.-P. J. Issa
High-throughput methylation profiling by MCA coupled to CpG island microarray
Genome Res., October 1, 2007; 17(10): 1529 - 1536.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Clin. Nutr.Home page
C. M Ulrich
Folate and cancer prevention: a closer look at a complex picture
Am. J. Clinical Nutrition, August 1, 2007; 86(2): 271 - 273.
[Full Text] [PDF]

Home page
 J AndrolHome page
K. Biermann and K. Steger
Epigenetics in Male Germ Cells
J Androl, July 1, 2007; 28(4): 466 - 480.
[Full Text] [PDF]

Home page
 JAMAHome page
C. M. Ulrich and J. D. Potter
Folate and Cancer--Timing Is Everything
JAMA, June 6, 2007; 297(21): 2408 - 2409.
[Full Text] [PDF]

Home page
 Molecular Cancer TherapeuticsHome page
T. Kiziltepe, T. Hideshima, L. Catley, N. Raje, H. Yasui, N. Shiraishi, Y. Okawa, H. Ikeda, S. Vallet, S. Pozzi, et al.
5-Azacytidine, a DNA methyltransferase inhibitor, induces ATR-mediated DNA double-strand break responses, apoptosis, and synergistic cytotoxicity with doxorubicin and bortezomib against multiple myeloma cells
Mol. Cancer Ther., June 1, 2007; 6(6): 1718 - 1727.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
A. Miremadi, M. Z. Oestergaard, P. D.P. Pharoah, and C. Caldas
Cancer genetics of epigenetic genes
Hum. Mol. Genet., April 15, 2007; 16(R1): R28 - R49.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
S. J. Clark
Action at a distance: epigenetic silencing of large chromosomal regions in carcinogenesis
Hum. Mol. Genet., April 15, 2007; 16(R1): R88 - R95.
[Abstract] [Full Text] [PDF]

Home page
 Neuro Oncol DukeHome page
R. Vibhakar, G. Foltz, J.-g. Yoon, L. Field, H. Lee, G.-y. Ryu, J. Pierson, B. Davidson, and A. Madan
Dickkopf-1 is an epigenetically silenced candidate tumor suppressor gene in medulloblastoma
Neuro-oncol, April 1, 2007; 9(2): 135 - 144.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Cell. Biol.Home page
R. Zhang, S.-t. Liu, W. Chen, M. Bonner, J. Pehrson, T. J. Yen, and P. D. Adams
HP1 Proteins Are Essential for a Dynamic Nuclear Response That Rescues the Function of Perturbed Heterochromatin in Primary Human Cells
Mol. Cell. Biol., February 1, 2007; 27(3): 949 - 962.
[Abstract] [Full Text] [PDF]

Home page
 J. Nutr.Home page
M. Fang, D. Chen, and C. S. Yang
Dietary Polyphenols May Affect DNA Methylation
J. Nutr., January 1, 2007; 137(1): 223S - 228S.
[Abstract] [Full Text] [PDF]

Home page
 Molecular Cancer TherapeuticsHome page
J.-H. Lee, J.-H. Park, Y. Jung, J.-H. Kim, H.-S. Jong, T.-Y. Kim, and Y.-J. Bang
Histone deacetylase inhibitor enhances 5-fluorouracil cytotoxicity by down-regulating thymidylate synthase in human cancer cells
Mol. Cancer Ther., December 1, 2006; 5(12): 3085 - 3095.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
N. C. Whitelaw and E. Whitelaw
How lifetimes shape epigenotype within and across generations
Hum. Mol. Genet., October 15, 2006; 15(suppl_2): R131 - R137.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Epidemiol. Biomarkers Prev.Home page
J. Young and J. R. Jass
The case for a genetic predisposition to serrated neoplasia in the colorectum: hypothesis and review of the literature.
Cancer Epidemiol. Biomarkers Prev., October 1, 2006; 15(10): 1778 - 1784.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
M. Dominguez
Interplay between Notch Signaling and Epigenetic Silencers in Cancer.
Cancer Res., September 15, 2006; 66(18): 8931 - 8934.
[Abstract] [Full Text] [PDF]

Home page
 Molecular Cancer TherapeuticsHome page
X. Qian, W. J. LaRochelle, G. Ara, F. Wu, K. D. Petersen, A. Thougaard, M. Sehested, H. S. Lichenstein, and M. Jeffers
Activity of PXD101, a histone deacetylase inhibitor, in preclinical ovarian cancer studies.
Mol. Cancer Ther., August 1, 2006; 5(8): 2086 - 2095.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Biol. CellHome page
A. Noer, A. L. Sorensen, A. C. Boquest, and P. Collas
Stable CpG Hypomethylation of Adipogenic Promoters in Freshly Isolated, Cultured, and Differentiated Mesenchymal Stem Cells from Adipose Tissue
Mol. Biol. Cell, August 1, 2006; 17(8): 3543 - 3556.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
G. Foltz, G.-Y. Ryu, J.-G. Yoon, T. Nelson, J. Fahey, A. Frakes, H. Lee, L. Field, K. Zander, Z. Sibenaller, et al.
Genome-Wide Analysis of Epigenetic Silencing Identifies BEX1 and BEX2 as Candidate Tumor Suppressor Genes in Malignant Glioma.
Cancer Res., July 1, 2006; 66(13): 6665 - 6674.
[Abstract] [Full Text] [PDF]

Home page
 GutHome page
S Ogino, M Cantor, T Kawasaki, M Brahmandam, G J Kirkner, D J Weisenberger, M Campan, P W Laird, M Loda, and C S Fuchs
CpG island methylator phenotype (CIMP) of colorectal cancer is best characterised by quantitative DNA methylation analysis and prospective cohort studies
Gut, July 1, 2006; 55(7): 1000 - 1006.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
W. K. Leung, E. P.S. Man, J. Yu, M. Y.Y. Go, K.-f. To, Y. Yamaoka, V. Y.Y. Cheng, E. K.W. Ng, and J. J.Y. Sung
Effects of Helicobacter pylori Eradication on Methylation Status of E-Cadherin Gene in Noncancerous Stomach.
Clin. Cancer Res., May 15, 2006; 12(10): 3216 - 3221.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
R. D. Hawkins and B. Ren
Genome-wide location analysis: insights on transcriptional regulation.
Hum. Mol. Genet., April 15, 2006; 15(suppl_1): R1 - R7.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
E. Yuan, F. Haghighi, S. White, R. Costa, J. McMinn, K. Chun, M. Minden, and B. Tycko
A single nucleotide polymorphism chip-based method for combined genetic and epigenetic profiling: validation in decitabine therapy and tumor/normal comparisons.
Cancer Res., April 1, 2006; 66(7): 3443 - 3451.
[Abstract] [Full Text] [PDF]

Home page
 Int J EpidemiolHome page
J. PEEDICAYIL
Genes underlying common complex diseases
Int. J. Epidemiol., April 1, 2006; 35(2): 490 - 491.
[Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
D. K. Vanaja, K. V. Ballman, B. W. Morlan, J. C. Cheville, R. M. Neumann, M. M. Lieber, D. J. Tindall, and C. Y.F. Young
PDLIM4 Repression by Hypermethylation as a Potential Biomarker for Prostate Cancer
Clin. Cancer Res., February 15, 2006; 12(4): 1128 - 1136.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
M. Herranz, J. Martin-Caballero, M. F. Fraga, J. Ruiz-Cabello, J. M. Flores, M. Desco, V. Marquez, and M. Esteller
The novel DNA methylation inhibitor zebularine is effective against the development of murine T-cell lymphoma
Blood, February 1, 2006; 107(3): 1174 - 1177.
[Abstract] [Full Text] [PDF]

Home page
 DNA ResHome page
J. Cheong, Y. Yamada, R. Yamashita, T. Irie, A. Kanai, H. Wakaguri, K. Nakai, T. Ito, I. Saito, S. Sugano, et al.
Diverse DNA Methylation Statuses at Alternative Promoters of Human Genes in Various Tissues
DNA Res, January 1, 2006; 13(4): 155 - 167.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
E. J. Noh, E. R. Jang, G. Jeong, Y. M. Lee, C. K. Min, and J.-S. Lee
Methyl CpG-Binding Domain Protein 3 Mediates Cancer-Selective Cytotoxicity by Histone Deacetylase Inhibitors via Differential Transcriptional Reprogramming in Lung Cancer Cells
Cancer Res., December 15, 2005; 65(24): 11400 - 11410.
[Abstract] [Full Text] [PDF]

Home page
 Nucleic Acids ResHome page
R. K. Neely, D. Daujotyte, S. Grazulis, S. W. Magennis, D. T. F. Dryden, S. Klimasauskas, and A. C. Jones
Time-resolved fluorescence of 2-aminopurine as a probe of base flipping in M.HhaI-DNA complexes
Nucleic Acids Res., December 9, 2005; 33(22): 6953 - 6960.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Epidemiol. Biomarkers Prev.Home page
C. M. Ulrich, K. Curtin, J. D. Potter, J. Bigler, B. Caan, and M. L. Slattery
Polymorphisms in the Reduced Folate Carrier, Thymidylate Synthase, or Methionine Synthase and Risk of Colon Cancer
Cancer Epidemiol. Biomarkers Prev., November 1, 2005; 14(11): 2509 - 2516.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
W. Sadee and Z. Dai
Pharmacogenetics/genomics and personalized medicine
Hum. Mol. Genet., October 15, 2005; 14(suppl_2): R207 - R214.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Laird, P. W.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Laird, P. W.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?