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MTA1-mediated transcriptional repression of BRCA1 tumor suppressor gene

Oncogene volume 27, pages 1971–1980 (2008)Cite this article

Abstract

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 α-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.

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Abbreviations

BRCA1 :

breast cancer susceptibility gene 1

ChIP:

chromatin immunoprecipitation

ERα:

estrogen receptor α

ERE:

estrogen-responsive element

HDAC:

histone deacetylase

MTA1:

metastasis- tumor antigen 1

NuRD complex:

nucleosome remodeling and deacetylase complex

TSA:

trichostatin A

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Acknowledgements

This study was supported by National Institutes of Health Grant CA 098823 and CA65746 to RK

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Authors and Affiliations

  1. Department of Molecular and Cellular Oncology, The University of Texas MD. Anderson Cancer Center, Houston, TX, USA

    P R Molli, R R Singh & R Kumar

  2. Harvard Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown, MA, USA

    S W Lee

  3. Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA

    R Kumar

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  1. P R Molli
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  2. R R Singh
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  4. R Kumar
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Correspondence to R Kumar.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Molli, P., Singh, R., Lee, S. et al. MTA1-mediated transcriptional repression of BRCA1 tumor suppressor gene. Oncogene 27, 1971–1980 (2008). https://doi.org/10.1038/sj.onc.1210839

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