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MTA1-mediated transcriptional repression of BRCA1 tumor suppressor gene

P R Molli1, R R Singh, S W Lee

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

Oncogene
|October 9, 2007
PubMed

Insights

Metastasis-associated tumor antigen 1 (MTA1) represses BRCA1 transcription, leading to abnormal cell division and chromosomal instability. Silencing MTA1 or using HDAC inhibitors restores BRCA1 levels and normalizes cell structures.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Metastasis-associated tumor antigen 1 (MTA1) is upregulated in various cancers.
  • MTA1 is a component of the nucleosome remodeling and deacetylating (NuRD) complex.
  • BRCA1 plays a crucial role in maintaining genomic stability.

Purpose of the Study:

  • To investigate the role of MTA1 in the transcriptional repression of BRCA1.
  • To explore the link between MTA1, BRCA1 repression, and chromosomal instability.
  • To understand the mechanism by which MTA1 affects BRCA1 expression.

Main Methods:

  • Investigated MTA1-NuRD complex interaction with the BRCA1 promoter.
  • Utilized estrogen receptor alpha (ER alpha) dependent recruitment assays.
  • Assessed BRCA1 protein levels after MTA1 silencing or HDAC inhibition (trichostatin A).
  • Analyzed centrosome numbers in cells with MTA1 or BRCA1 overexpression.

Main Results:

  • MTA1-NuRD complex physically associates with an atypical estrogen-responsive element (ERE) on the BRCA1 promoter.
  • MTA1 and HDAC complex are recruited to the BRCA1 promoter ERE in an ER alpha-dependent manner.
  • Silencing MTA1 or inhibiting histone deacetylase (HDAC) increased BRCA1 protein levels.
  • Overexpression of MTA1 led to centrosome amplification, a phenotype reversed by BRCA1 re-expression.

Conclusions:

  • MTA1 transcriptionally represses BRCA1 via the NuRD complex and ER alpha.
  • MTA1-mediated BRCA1 repression contributes to abnormal centrosome numbers.
  • These findings implicate MTA1 in promoting chromosomal instability in cancer.

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