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In Vitro Ubiquitination and Deubiquitination Assays of Nucleosomal Histones
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A carboxy-terminal ubiquitylation site regulates androgen receptor activity

Seiji Arai1,2, Yanfei Gao1,3, Ziyang Yu1

  • 1Department of Medicine and Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.

Communications Biology
|January 5, 2024
PubMed

Insights

Proteasome inhibition stabilizes androgen receptor (AR) in prostate cancer. New research identifies novel AR modification sites, including K911, impacting AR stability and activity.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Biochemistry

Background:

  • Androgen receptor (AR) degradation is crucial in prostate cancer therapy.
  • Proteasome inhibition stabilizes AR but with limited impact on polyubiquitylation.
  • Deubiquitylase inhibitors do not increase unliganded AR ubiquitylation, suggesting AR is not a direct target.

Purpose of the Study:

  • To investigate the posttranslational modifications of the androgen receptor (AR).
  • To identify novel ubiquitylation sites on AR and their functional consequences.
  • To explore the regulatory roles of distinct posttranslational modifications on AR activity.

Main Methods:

  • Proteasome inhibition and deubiquitylase inhibition experiments.
  • Identification of AR ubiquitylation, methylation, and phosphorylation sites.
  • Site-directed mutagenesis of identified AR modification sites (K911, K313, K318).

Main Results:

  • A novel ubiquitylation site, K911, was identified on the androgen receptor.
  • Mutagenesis of K911 enhanced AR stability, chromatin binding, and transcriptional activity.
  • The K313 site, previously known for ubiquitylation, also undergoes methylation and acetylation, differentially regulating AR activity.

Conclusions:

  • This study expands the known spectrum of androgen receptor posttranslational modifications.
  • The K911 site emerges as a key regulator of AR stability and turnover on chromatin.
  • Distinct posttranslational modifications at K313 provide differential regulation of AR transcriptional activity.

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