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Differential modulation of androgen receptor transcriptional activity by the nuclear receptor co-repressor (N-CoR)

Cor A Berrevoets1, Arzu Umar, Jan Trapman

  • 1Department of Reproduction and Development, Erasmus MC, University Medical Center Rotterdam, 3000 DR Rotterdam, Netherlands. c.berrevoets@erasmusmc.nl

The Biochemical Journal
|January 28, 2004
PubMed

Insights

Nuclear receptor co-repressor N-CoR regulates androgen receptor (AR) activity differently with various ligands. N-CoR represses antiandrogen activity, especially on mutant AR, impacting prostate cancer treatment.

Area of Science:

  • Molecular Biology
  • Endocrinology
  • Cancer Research

Background:

  • Antiandrogens are crucial for prostate cancer treatment by inhibiting androgen receptor (AR) action.
  • The precise mechanisms of antiandrogen action are not fully understood, but nuclear receptor co-repressors are implicated.
  • Nuclear receptor co-repressor (N-CoR) plays a role in regulating AR transcriptional activity.

Purpose of the Study:

  • To investigate the regulation of AR transcriptional activity by N-CoR in the presence of different ligands.
  • To understand how N-CoR affects AR activity with agonists versus antagonists.
  • To examine the influence of N-CoR on AR activity in the context of prostate cancer-associated mutations.

Main Methods:

  • Investigated AR transcriptional activity using co-transfection assays with varying N-CoR levels.
  • Tested the effects of different ligands, including agonists (R1881) and partial agonists/antagonists (cyproterone acetate [CPA], mifepristone [RU486]).
  • Examined the interplay between N-CoR, co-activator TIF2, and wild-type versus T877A mutant AR.

Main Results:

  • N-CoR repressed CPA- and RU486-mediated AR activity at low levels, but not R1881-induced activity.
  • Higher N-CoR levels repressed AR activity for all ligands and converted partial agonists into antagonists.
  • TIF2 relieved N-CoR repression for agonists but not for antagonists, indicating antagonist-bound AR preference for N-CoR.
  • The T877A AR mutation significantly reduced N-CoR repression, allowing antiandrogens to act as agonists.

Conclusions:

  • N-CoR differentially regulates AR transcriptional activity based on ligand type and concentration.
  • Antagonist-bound AR shows a preference for N-CoR over co-activator TIF2.
  • The T877A mutation in AR diminishes N-CoR's repressive function, potentially leading to antiandrogen agonism in prostate cancer.

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