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A genome-wide RNA interference screen identifies new regulators of androgen receptor function in prostate cancer

Keren Imberg-Kazdan1, Susan Ha, Alex Greenfield

  • 1Department of Biochemistry, New York University School of Medicine, New York, New York 10016, USA.

Genome Research
|February 14, 2013
PubMed

Insights

Researchers identified new genes controlling androgen receptor (AR) activity in prostate cancer. Targeting HIPK2 and MED19 reduced cancer cell growth, offering potential new treatments for castration-resistant prostate cancer.

Area of Science:

  • Molecular Biology
  • Genetics
  • Cancer Research

Background:

  • The androgen receptor (AR) drives both androgen-dependent and castration-resistant prostate cancers.
  • Identifying factors regulating AR transcriptional activity is crucial for developing new prostate cancer therapies.
  • A comprehensive analysis of genes essential for AR activity has been lacking.

Purpose of the Study:

  • To conduct a genome-wide screen for genes regulating AR transcriptional activity.
  • To identify novel cellular factors and potential therapeutic targets for prostate cancer.
  • To investigate the role of specific regulators, like HIPK2 and MED19, in prostate cancer cell proliferation.

Main Methods:

  • Utilized an unbiased, evolutionarily conserved genetic approach using a genome-wide RNAi screen in Drosophila cells.
  • Applied findings from the Drosophila screen to human prostate cancer cells.
  • Systematically analyzed Mediator complex subunits and tested FDA-approved kinase inhibitors.

Main Results:

  • Identified 45 novel AR regulators, including HIPK2 and MED19, not previously linked to AR regulation.
  • Depletion of HIPK2 and MED19 decreased AR target gene expression and reduced proliferation in both androgen-dependent and castration-resistant prostate cancer cells.
  • Targeting HIPK2 with an FDA-approved inhibitor reduced the growth of AR-positive, treatment-resistant prostate cancer cells.

Conclusions:

  • The study identified novel AR regulators, including drugable targets like HIPK2.
  • These findings provide new therapeutic strategies to combat castration-resistant prostate cancer by targeting AR signaling.
  • The research highlights the potential of conserved genetic screens for discovering cancer-related genes and drug targets.

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