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A transcriptional repressor co-regulatory network governing androgen response in prostate cancers

Kern Rei Chng1, Cheng Wei Chang, Si Kee Tan

  • 1Cancer Biology and Pharmacology, Genome Institute of Singapore, A*STAR, Singapore.

The EMBO Journal
|April 26, 2012
PubMed

Insights

Oncogenic corepressors like HDACs and EZH2, alongside ERG, directly repress Androgen Receptor (AR) target genes. This mechanism promotes prostate cancer progression by hindering differentiation and increasing cell invasiveness.

Area of Science:

  • Molecular Oncology
  • Cancer Biology
  • Epigenetics

Background:

  • Transcriptional corepressors are often over-expressed in prostate cancer.
  • The interaction between corepressors and the Androgen Receptor (AR) in prostate cancer is not well understood.

Purpose of the Study:

  • To investigate the crosstalk between AR and key transcriptional corepressors (HDAC1, HDAC2, HDAC3, EZH2) in prostate cancer.
  • To elucidate the role of these corepressors and ERG in AR-regulated transcription and prostate cancer progression.

Main Methods:

  • Chromatin immunoprecipitation followed by sequencing (ChIP-Seq) was used to map the binding sites of AR, ERG, HDAC1, HDAC2, HDAC3, and EZH2.
  • Analysis of global binding patterns in prostate cancer cells.

Main Results:

  • ERG, HDACs, and EZH2 are directly involved in androgen-regulated transcription, forming an AR-centric network.
  • These corepressors mediate the repression of AR-induced genes, including those involved in epithelial differentiation and metastasis suppression.
  • Suppression of Vinculin expression by ERG, EZH2, and HDACs correlates with increased prostate cancer cell invasiveness.

Conclusions:

  • ERG, in conjunction with oncogenic corepressors (HDACs, EZH2), impedes epithelial differentiation.
  • This interaction contributes to prostate cancer progression by modulating AR transcriptional output and enhancing cell invasiveness.

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