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Hormonal control of androgen receptor function through SIRT1

Maofu Fu1, Manran Liu, Anthony A Sauve

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

Molecular and Cellular Biology
|August 23, 2006
PubMed

Insights

SIRT1 antagonists boost androgen receptor (AR) expression and signaling in prostate cancer. SIRT1 directly deacetylates AR, inhibiting DHT-induced growth and linking sirtuins to prostate cancer progression.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • Sir2 (SIRT1) is an NAD-dependent deacetylase linking metabolism, gene silencing, and aging.
  • The androgen receptor (AR) regulates prostate cancer cell functions in response to androgens like dihydrotestosterone (DHT).

Purpose of the Study:

  • To investigate the role of SIRT1 in regulating androgen receptor (AR) signaling in prostate cancer.
  • To determine if SIRT1 directly interacts with and modifies the AR.

Main Methods:

  • Utilized SIRT1 antagonists to observe effects on AR expression and signaling.
  • Performed biochemical assays to confirm SIRT1 binding and deacetylation of AR.
  • Assessed the impact of SIRT1 on AR-mediated gene expression and cellular growth.

Main Results:

  • SIRT1 antagonists increased endogenous AR expression and enhanced DHT-induced AR signaling.
  • SIRT1 directly binds to and deacetylates the AR at a specific lysine motif.
  • SIRT1's catalytic activity and AR deacetylation are necessary for inhibiting DHT-induced AR signaling.
  • SIRT1 repressed coactivator interactions with AR and blocked DHT-induced prostate cancer cell growth.

Conclusions:

  • SIRT1 directly regulates AR activity through deacetylation.
  • SIRT1 acts as a negative regulator of AR signaling and prostate cancer cell growth.
  • This study establishes a functional link between sirtuins and AR in prostate cancer progression.

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