Human Molecular Genetics Advance Access originally published online on February 24, 2005
Human Molecular Genetics 2005 14(7):973-982; doi:10.1093/hmg/ddi091
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Transcriptional targets of the chromatin-remodelling factor SMARCA4/BRG1 in lung cancer cells
1Lung Cancer Group and 2Cancer Epigenetics Group, Molecular Pathology Programme, Spanish National Cancer Centre (CNIO), Madrid, Spain and 3Pathology Department, Hospital Universitario 12 de Octubre, Madrid, Spain
* To whom correspondence should be addressed at: Molecular Pathology Programme, Spanish National Cancer Centre (CNIO), C/Melchor Fernandez Almagro 3, 28029 Madrid, Spain. Tel: +34 912246954; Fax: +34 912246923; Email: msanchez{at}cnio.es
Received January 13, 2005; Accepted February 17, 2005
BRG1, also called SMARCA4, is the catalytic subunit of the SWI/SNF chromatin-remodelling complex and influences transcriptional regulation by disrupting histone–DNA contacts in an ATP-dependent manner. BRG1 and other members of the SWI/SNF complex become inactivated in tumours, implying a role in cancer development. To understand the contribution of BRG1 to lung tumourigenesis, we restored BRG1 in H1299 lung cancer cells and used cDNA microarray analysis to identify changes in gene expression. Forty-three transcripts became activated, whereas two were repressed. Chromatin immunoprecipitation of resulting candidate genes revealed that the CYP3A4 and ZNF185 promoters recruited BRG1 and that recruitment to the CYP3A4 promoter was specific to this gene and did not involve the CYP3A5 or CYP3A7 family members. Moreover, specifically BRG1 but not its homologue BRM was recruited to the CYP3A4 and ZNF185 promoters. To explore their potential relevance in lung tumours, levels of CYP3A4 and ZNF185 transcripts were evaluated in seven additional lung cancer cell lines. CYP3A4 was undetectable in any of the lung cancer cells tested, and only the CYP3A5 family member was present in the A549 and Calu-3 cells. In contrast, the amount of ZNF185 transcript clearly varied among lung cancer cell lines and severely reduced levels were observed in BRG1-deficient cells, except those of A427. We extended these observations to 27 lung primary tumours using real-time RT–PCR (TaqMan) and observed that four (15%) and 14 (52%) of them had BRG1 and ZNF185 downregulation, respectively, when compared with normal lung. No significant correlation between reduced levels of BRG1 and ZNF185 was observed, indicating that additional mechanisms to BRG1 inactivation may contribute to the loss of ZNF185 expression in lung tumours. In conclusion, our results provide evidence that transcriptional activation of ZNF185 and CYP3A4 is mediated by direct association of BRG1 with their promoters and also indicate that a decreased level of ZNF185 is a common feature of lung tumours and may be of biological relevance in lung carcinogenesis.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  P. P. Medina, S. D. Castillo, S. Blanco, M. Sanz-Garcia, C. Largo, S. Alvarez, J. Yokota, A. Gonzalez-Neira, J. Benitez, H. C. Clevers, et al. The SRY-HMG box gene, SOX4, is a target of gene amplification at chromosome 6p in lung cancer Hum. Mol. Genet., April 1, 2009; 18(7): 1343 - 1352. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Rodriguez-Nieto and M. Sanchez-Cespedes BRG1 and LKB1: tales of two tumor suppressor genes on chromosome 19p and lung cancer Carcinogenesis, April 1, 2009; 30(4): 547 - 554. [Abstract] [Full Text] [PDF]
|
|