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Inhibition of cyclin D1 gene transcription by Brg-1

Mahadev Rao1, Mathew C Casimiro, Michael P Lisanti

  • 1Kimmel Cancer Center, Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.

Cell Cycle (Georgetown, Tex.)
|February 2, 2008
PubMed

Insights

BRG-1, a subunit of the SWI-SNF complex, suppresses breast cancer cell proliferation by inhibiting DNA synthesis and cyclin D1 expression. It acts as a scaffold on the cyclin D1 promoter, regulating gene expression.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • The SWI-SNF chromatin remodeling complex is crucial for regulating cellular proliferation.
  • BRG-1, a catalytic subunit of SWI-SNF, is often altered in malignant cells, but its tumor suppressor role in breast cancer is unclear.
  • Cyclin D1 is an oncogene overexpressed in over 50% of human breast cancers.

Purpose of the Study:

  • To investigate the mechanism by which BRG-1 suppresses breast cancer cell proliferation.
  • To determine if BRG-1 inhibits DNA synthesis and cyclin D1 expression in breast cancer cells.
  • To elucidate the role of BRG-1 in regulating the cyclin D1 gene promoter.

Main Methods:

  • Promoter assays were used to assess BRG-1's effect on cyclin D1 expression.
  • RNA interference (siRNA) and cell deficiency models were employed to study BRG-1's role in chromatin complex formation.
  • Chromatin immunoprecipitation (ChIP) assays were performed to detect BRG-1 binding to the cyclin D1 promoter and estradiol-induced recruitment.
  • Analysis of co-repressor recruitment (HP1alpha/HDAC1) to the cyclin D1 promoter was conducted.

Main Results:

  • BRG-1 significantly inhibited DNA synthesis and cyclin D1 expression in MCF-7 breast cancer cells.
  • The repression of cyclin D1 by BRG-1 required AP-1 and CRE sites in the promoter.
  • BRG-1 deficiency or siRNA knockdown reduced the formation of BRG-1 chromatin complexes.
  • Endogenous BRG-1 was found to bind to the AP-1 site of the cyclin D1 promoter.
  • Estradiol treatment induced BRG-1 recruitment to the hpS2 gene promoter and reduced co-repressor recruitment to the cyclin D1 promoter's AP-1/BRG-1 sites.

Conclusions:

  • BRG-1 acts as a tumor suppressor by inhibiting breast cancer cell proliferation.
  • BRG-1 directly binds to the cyclin D1 promoter and regulates its expression.
  • The cyclin D1 promoter serves as a scaffold for recruiting coactivators and corepressors, mediated by BRG-1, to control gene expression.

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