Potent Stimulation of the Androgen Receptor Instigates a Viral Mimicry Response in Prostate Cancer

Mohammadreza Alizadeh-Ghodsi, Katie L. Owen, Scott L. Townley, Damien Zanker, Samuel P.G. Rollin, Adrienne R. Hanson, Raj Shrestha, John Toubia, Tessa Gargett, Igor Chernukhin, Jennii Luu, Karla J. Cowley, Ashlee Clark, Jason S. Carroll, Kaylene J. Simpson, Jean M. Winter, Mitchell G. Lawrence, Lisa M. Butler, Gail P. Risbridger, Benjamin ThierryRenea A. Taylor, Theresa E. Hickey, Belinda S. Parker, Wayne D. Tilley, Luke A. Selth

Research output: Contribution to journalArticleResearchpeer-review

9 Citations (Scopus)

Abstract

Inhibiting the androgen receptor (AR), a ligand-activated transcription Increased ERV expression led to accumulation of double-stranded RNA factor, with androgen deprivation therapy is a standard-of-care treatment and a “viral mimicry” response characterized by activation of IFN signal-for metastatic prostate cancer. Paradoxically, activation of AR can also ing, upregulation of MHC class I molecules, and enhanced recognition of inhibit the growth of prostate cancer in some patients and experimen- murine prostate cancer cells by CD8+ T cells. Positive associations between tal systems, but the mechanisms underlying this phenomenon are poorly AR activity and ERVs/antiviral pathways were evident in patient transcripunderstood. This study exploited a potent synthetic androgen, methyl- tomic data, supporting the clinical relevance of our findings. Collectively, testosterone (MeT), to investigate AR agonist-induced growth inhibition. our study reveals that the potent androgen MeT can increase the immunoMeT strongly inhibited growth of prostate cancer cells expressing AR, genicity of prostate cancer cells via a viral mimicry response, a finding that but not AR-negative models. Genes and pathways regulated by MeT were has potential implications for the development of strategies to sensitize this highly analogous to those regulated by DHT, although MeT induced a cancer type to immunotherapies. quantitatively greater androgenic response in prostate cancer cells. MeT Significance:Our study demonstrates that potent androgen stimulation potently downregulated DNA methyltransferases, leading to global DNA of prostate cancer cells can elicit a viral mimicry response, resulting hypomethylation. These epigenomic changes were associated with dys- in enhanced IFN signaling. This finding may have implications for the regulation of transposable element expression including upregulation of development of strategies to sensitize prostate cancer to immunotherapies. endogenous retrovirus (ERV) transcripts after sustained MeT treatment.

Original languageEnglish
Pages (from-to)706-724
Number of pages19
JournalCancer Research Communications
Volume2
Issue number7
DOIs
Publication statusPublished - Jul 2022

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