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Updated: Jul 31, 2025

Murine Prostate Micro-dissection and Surgical Castration
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TRAF4-mediated nonproteolytic ubiquitination of androgen receptor promotes castration-resistant prostate cancer

Ramesh Singh1, Huan Meng1, Tao Shen1

  • 1Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030.

Proceedings of the National Academy of Sciences of the United States of America
|May 8, 2023
PubMed

Insights

TRAF4 E3 ligase drives castration-resistant prostate cancer (CRPC) by altering androgen receptor (AR) binding. This atypical ubiquitination promotes AR

Area of Science:

  • Molecular Oncology
  • Cancer Biology
  • Ubiquitination Signaling

Background:

  • Castration-resistant prostate cancer (CRPC) remains a clinical challenge, with the androgen receptor (AR) as a key driver.
  • AR induces distinct transcriptional programs in CRPC after androgen deprivation, but the underlying mechanisms are unclear.
  • Understanding AR's genomic binding and its role in CRPC development is crucial for therapeutic strategies.

Purpose of the Study:

  • To elucidate the mechanism by which AR binds to distinct genomic loci in CRPC.
  • To investigate the role of atypical ubiquitination in AR-mediated transcriptional reprogramming in CRPC.
  • To identify novel therapeutic targets for castration-resistant prostate cancer.

Main Methods:

  • Investigated the role of E3 ubiquitin ligase TRAF4 in CRPC development.
  • Analyzed AR ubiquitination status, specifically K27-linked ubiquitination, and its effect on AR-FOXA1 interaction.
  • Examined AR binding to genomic loci and subsequent transcriptional changes, including olfactory transduction pathways.

Main Results:

  • TRAF4 is highly expressed in CRPC and promotes tumor development.
  • TRAF4 mediates K27-linked ubiquitination of AR, enhancing its association with FOXA1.
  • TRAF4-mediated AR reprogramming drives olfactory receptor gene transcription, increasing cAMP and E2F activity, promoting proliferation in castration conditions.

Conclusions:

  • Atypical ubiquitination of AR by TRAF4 is a key posttranslational mechanism driving AR-regulated transcriptional reprogramming in CRPC.
  • TRAF4 facilitates AR binding to specific genomic sites, promoting cell survival and proliferation under androgen deprivation.
  • Targeting TRAF4-mediated ubiquitination may offer a novel therapeutic strategy for castration-resistant prostate cancer.
Keywords:
CRPCE2FTRAF4androgen receptorubiquitination

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