TRAF4-mediated nonproteolytic ubiquitination of androgen receptor promotes castration-resistant prostate cancer.

Authors

Ramesh Singh
Huan Meng
Tao Shen
Lance Edward V Lumahan
Steven Nguyen
Hong Shen
Subhamoy Dasgupta
Li Qin
Dileep Karri
Bokai Zhu
Feng Yang
Cristian Coarfa
Bert W O'Malley
Ping Yi

Publication Date

5-16-2023

Journal

Proceedings of the National Academy of Sciences of the United States of America

DOI

10.1073/pnas.2218229120

PMID

37155905

PMCID

PMC10193960

PubMedCentral® Posted Date

5-8-2023

PubMedCentral® Full Text Version

Post-Print

Published Open-Access

no

Keywords

Male, Humans, Receptors, Androgen, Prostatic Neoplasms, Castration-Resistant, Androgens, Androgen Antagonists, TNF Receptor-Associated Factor 4, Cell Line, Tumor, Ubiquitination, Gene Expression Regulation, Neoplastic

Abstract

Castration-resistant prostate cancer (CRPC) poses a major clinical challenge with the androgen receptor (AR) remaining to be a critical oncogenic player. Several lines of evidence indicate that AR induces a distinct transcriptional program after androgen deprivation in CRPCs. However, the mechanism triggering AR binding to a distinct set of genomic loci in CRPC and how it promotes CRPC development remain unclear. We demonstrate here that atypical ubiquitination of AR mediated by an E3 ubiquitin ligase TRAF4 plays an important role in this process. TRAF4 is highly expressed in CRPCs and promotes CRPC development. It mediates K27-linked ubiquitination at the C-terminal tail of AR and increases its association with the pioneer factor FOXA1. Consequently, AR binds to a distinct set of genomic loci enriched with FOXA1- and HOXB13-binding motifs to drive different transcriptional programs including an olfactory transduction pathway. Through the surprising upregulation of olfactory receptor gene transcription, TRAF4 increases intracellular cAMP levels and boosts E2F transcription factor activity to promote cell proliferation under androgen deprivation conditions. Altogether, these findings reveal a posttranslational mechanism driving AR-regulated transcriptional reprogramming to provide survival advantages for prostate cancer cells under castration conditions.

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