Androgen receptor variants: RNA-based mechanisms and therapeutic targets

Kiel T. Tietz, Scott M. Dehm

Research output: Contribution to journalReview articlepeer-review

Abstract

Prostate cancer is the second leading cause of male cancer death in the United States. The androgen receptor (AR) transcription factor is a master regulator of normal glandular homeostasis in the prostate, as well as growth and survival of prostate cancer cells. Therefore, AR-targeted therapies are effective for improving overall survival of patients with advanced prostate cancer that is incurable by surgery or radiation. However, prostate cancer will inevitably progress on AR-targeted therapies to a castration-resistant prostate cancer (CRPC) phenotype that accounts for virtually all prostate cancer-specific death. mRNA transcript variants of the AR gene are expressed in CRPC cells and can be translated to produce AR variant (AR-V) proteins that function as ligand-independent, constitutively active transcription factors. AR-Vs are able to support growth of CRPC cells by promoting expression of AR target genes that are normally suppressed by AR-targeted therapies. Knowledge of mechanisms that govern expression of AR-Vs is incomplete. Studies have shown genomic rearrangements of the AR gene underlie expression of diverse AR-Vs in certain CRPC tumors, but post-transcriptional processes represent a broader regulatory mechanism for expression of AR-Vs in CRPC. This review focuses on alternative splicing, 3' end processing, miRNA-mediated mRNA repression, of AR and AR-V expression and the potential these mechanisms hold as therapeutic targets for CRPC.

Original languageEnglish (US)
Pages (from-to)R19-R26
JournalHuman molecular genetics
Volume29
DOIs
StatePublished - Sep 15 2020

Bibliographical note

Funding Information:
National Institutes of Health (grant R01CA174777 to S.M.D.); Kiel Tietz was supported by T32 CA009138.

Publisher Copyright:
© The Author(s) 2020. Published by Oxford University Press. All rights reserved.

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Review

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