MTA1-mediated transcriptional repression of BRCA1 tumor suppressor gene.
Metastasis-associated tumor antigen 1 (MTA1), a component of the nucleosome remodeling and deacetylating (NuRD) complex is routinely upregulated in several cancers. In the present study, we investigated the potential role of MTA1 in BRCA1 transcriptional repression and subsequent chromosomal instability. MTA1-NuRD complex was found to negatively regulate BRCA1 transcription by physically associating with an atypical estrogen-responsive element (ERE) on the BRCA1 promoter. Moreover, MTA1 and HDAC complex recruited to the ERE of BRCA1 promoter in an ER alpha-dependent manner. Accordingly, BRCA1 protein levels were enhanced by silencing of either MTA1 expression or by treatment with the specific histone deacetylase inhibitor trichostatin A. MTA1's strong repressive effects on BRCA1 expression was supported by our observation that cells stably overexpressing MTA1 showed centrosome amplification which has been long implicated as a phenotype for BRCA1 repression. Accordingly, overexpression of BRCA1 in cells stably over expressing MTA1 resulted in restoration of normal centrosome numbers. Together, these findings strongly implicate MTA1 in the transcriptional repression of BRCA1 leading to abnormal centrosome number and chromosomal instability.
Molli
P R
PR
Department of Molecular and Cellular Oncology, The University of Texas MD. Anderson Cancer Center, Houston, TX, USA.
Singh
R R
RR
Lee
S W
SW
Kumar
R
R
D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology; D018385:Centrosome / Q000378:metabolism* / Q000648:ultrastructure; D043171:Chromosomal Instability / Q000235:genetics*; D015536:Down-Regulation; D047628:Estrogen Receptor alpha / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D019398:Genes, BRCA1; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements; D015534:Trans-Activators; D014158:Transcription, Genetic
D047628:Estrogen Receptor alpha; C089320:MTA1 protein, human; D012097:Repressor Proteins; D015534:Trans-Activators; D006655:Histone Deacetylases; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex