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Requirement for chromatin-remodeling complex in novel tumor suppressor HIC1-mediated transcriptional repression and

B Zhang1, K J Chambers, D Leprince

  • 1Cancer Research Center, Boston University School of Medicine, Boston, MA 02118, USA.

Oncogene
|November 19, 2008
PubMed

Insights

The tumor suppressor HIC1 (Hypermethylated In Cancer 1) regulates cell growth by targeting E2F genes. Its function depends on Brg1, a chromatin remodeler, revealing a new pathway critical for preventing cancer.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Epigenetics

Background:

  • Hypermethylated In Cancer 1 (HIC1) is a tumor suppressor frequently silenced in human cancers.
  • HIC1 protein expression correlates with improved outcomes in breast cancer patients.
  • The precise molecular mechanisms of HIC1-mediated transcriptional repression and growth suppression remain largely undefined.

Purpose of the Study:

  • To elucidate the molecular mechanism of HIC1-mediated transcriptional regulation and growth suppression.
  • To identify specific gene targets regulated by HIC1.
  • To investigate the interaction between HIC1 and the SWI/SNF chromatin remodeler Brg1.

Main Methods:

  • Identification of HIC1 DNA-binding sites within E2F-responsive gene promoters.
  • Analysis of HIC1's interaction with and dependence on Brg1 activity.
  • Assessment of HIC1's role in transcriptional regulation and growth suppression of target genes.

Main Results:

  • HIC1 binds to E2F-responsive gene promoters, regulating their transcription and mediating growth suppression.
  • HIC1 recruits the Brg1 protein, a key component of the SWI/SNF chromatin-remodeling complex, to these promoters.
  • HIC1-mediated transcriptional repression of E2F-responsive genes is dependent on Brg1 activity.

Conclusions:

  • HIC1 functions as a central regulator in a novel pathway controlling cell growth.
  • HIC1 utilizes Brg1 to repress the transcription of E2F-responsive genes.
  • Disruption of this HIC1-Brg1 pathway can lead to uncontrolled cell proliferation and cancer development.

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