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Reverse Yeast Two-hybrid System to Identify Mammalian Nuclear Receptor Residues that Interact with Ligands and/or Antagonists
Published on: November 15, 2013
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
Summary
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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