Skip Navigation



Human Molecular Genetics Advance Access published online on September 22, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddh298
© 2004 by Oxford University Press
This Article
Right arrow Advance Access manuscript (PDF) Freely available
Right arrow All Versions of this Article:
13/22/2753    most recent
ddh298v1
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 Ropero, S.
Right arrow Articles by Esteller, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Ropero, S.
Right arrow Articles by Esteller, M.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Article

Epigenetic loss of the familial tumor-suppressor gene exostosin-1 (EXT1) disrupts heparan sulfate synthesis in cancer cells

Santiago Ropero 1, Fernando Setien 1, Jesus Espada 1, Mario F. Fraga 1, Michel Herranz 1, Julia Asp 2, Maria Serena Benassi 3, Alessandro Franchi 4, Ana Patiño 5, Laura S. Ward 6, Judith Bovee 7, Juan C. Cigudosa 8, Wuyts Wim 9, and Manel Esteller 1*

1 Cancer Epigenetics Laboratory, Spanish National Cancer Centre (CNIO), Melchor Fernandez Almagro 3, 28029 Madrid, Spain
2 Department of Clinical Chemistry and Transfusion Medicine, Research Center for Endocrinology and Metabolism, Institution of Laboratory Medicine, Sahlgrenska University Hospital, Goteborg, Sweden
3 Department of Musculoskeletal Oncology, Laboratory of Oncologic Research, Rizzoli Orthopedic Institute, Bologna, Italy
4 Department of Human Pathology and Oncology, Universita Degli Studi di Firenze, Italy
5 Department of Pediatrics, Clinica Universitaria de Navarra, Pamplona, Spain
6 Laboratory of Molecular Genetics of Cancer - GEMOCA, School of Medicine, Sao Paulo, Brasil
7 Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands
8 Cytogenetics Laboratory, Spanish National Cancer Centre (CNIO), Melchor Fernandez Almagro 3, 28029 Madrid, Spain
9 Department of Medical Genetics, University of Antwerp, Universiteitsplein 1, Building T, 6th floor, 2610 Antwerp, Belgium

* To whom correspondence should be addressed. E-mail: mesteller{at}cnio.es.


  Abstract

Germline mutations in the Exostoses-1 gene (EXT1) are found in hereditary multiple exostoses (HME) syndrome, which is characterized by the formation of osteochondromas and an increased risk of chondrosarcomas and osteosarcomas. However, despite its putative tumor-suppressor function, little is known of the contribution of EXT1 to human sporadic malignancies. Here, we report that EXT1 function is abrogated in human cancer cells by transcriptional silencing associated with CpG island-promoter hypermethylation. We also show that, at the biochemical and cellular levels, the epigenetic inactivation of EXT1, a glycosyltransferase, leads to the loss of heparan sulfate synthesis. Reduced heparan sulfate production can be reversed by the use of a DNA demethylating agent. Furthermore, the reintroduction of EXT1 into cancer-cell lines displaying methylation-dependent silencing of EXT1 induces tumor-suppressor-like features, e.g., reduced colony formation density and tumor growth in nude mouse xenograft models. Screening a large collection of human cancer-cell lines (n=79) and primary tumors (n=454) from different cell types, we found that EXT1 CpG island hypermethylation was common in leukemia, especially acute promyelocytic leukemia and acute lymphoblastic leukemia, and non-melanoma skin cancer. These findings highlight the importance of EXT1 epigenetic inactivation, leading to an abrogation of heparan sulfate biosynthesis, in the processes of tumor onset and progression.


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
 J BiochemHome page
S. Nadanaka and H. Kitagawa
Heparan Sulphate Biosynthesis and Disease
J. Biochem., July 1, 2008; 144(1): 7 - 14.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
M. Esteller
Epigenetic gene silencing in cancer: the DNA hypermethylome
Hum. Mol. Genet., April 15, 2007; 16(R1): R50 - R59.
[Abstract] [Full Text] [PDF]

Home page
 JNCI J Natl Cancer InstHome page
L. Hameetman, K. Szuhai, A. Yavas, J. Knijnenburg, M. van Duin, H. van Dekken, A. H. M. Taminiau, A.-M. Cleton-Jansen, J. V. M. G. Bovee, and P. C. W. Hogendoorn
The Role of EXT1 in Nonhereditary Osteochondroma: Identification of Homozygous Deletions
J Natl Cancer Inst, March 7, 2007; 99(5): 396 - 406.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
K. Mrozek, G. Marcucci, P. Paschka, S. P. Whitman, and C. D. Bloomfield
Clinical relevance of mutations and gene-expression changes in adult acute myeloid leukemia with normal cytogenetics: are we ready for a prognostically prioritized molecular classification?
Blood, January 15, 2007; 109(2): 431 - 448.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
R. Agrelo, W.-H. Cheng, F. Setien, S. Ropero, J. Espada, M. F. Fraga, M. Herranz, M. F. Paz, M. Sanchez-Cespedes, M. J. Artiga, et al.
Epigenetic inactivation of the premature aging Werner syndrome gene in human cancer
PNAS, June 6, 2006; 103(23): 8822 - 8827.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
M. C. Lemos, P. Kotanko, P. T. Christie, B. Harding, T. Javor, C. Smith, R. Eastell, and R. V. Thakker
A Novel EXT1 Splice Site Mutation in a Kindred with Hereditary Multiple Exostosis and Osteoporosis
J. Clin. Endocrinol. Metab., September 1, 2005; 90(9): 5386 - 5392.
[Abstract] [Full Text] [PDF]

Home page
 JCOHome page
R. Agrelo, F. Setien, J. Espada, M. J. Artiga, M. Rodriguez, A. Perez-Rosado, A. Sanchez-Aguilera, M. F. Fraga, M. A. Piris, and M. Esteller
Inactivation of the Lamin A/C Gene by CpG Island Promoter Hypermethylation in Hematologic Malignancies, and Its Association With Poor Survival in Nodal Diffuse Large B-Cell Lymphoma
J. Clin. Oncol., June 10, 2005; 23(17): 3940 - 3947.
[Abstract] [Full Text] [PDF]


Disclaimer:
Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.