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

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dc.contributor.authorA, M.
dc.contributor.authorOwen, K.L.
dc.contributor.authorTownley, S.
dc.contributor.authorZanker, D.
dc.contributor.authorRollin, S.P.G.
dc.contributor.authorHanson, A.R.
dc.contributor.authorShrestha, R.
dc.contributor.authorToubia, J.
dc.contributor.authorGargett, T.
dc.contributor.authorChernukhin, I.
dc.contributor.authorLuu, J.
dc.contributor.authorCowley, K.J.
dc.contributor.authorClark, A.
dc.contributor.authorCarroll, J.S.
dc.contributor.authorSimpson, K.J.
dc.contributor.authorWinter, J.M.
dc.contributor.authorLawrence, M.G.
dc.contributor.authorButler, L.M.
dc.contributor.authorRisbridger, G.P.
dc.contributor.authorThierry, B.
dc.contributor.authoret al.
dc.date.issued2022
dc.description.abstractInhibiting the androgen receptor (AR), a ligand-activated transcription factor, with androgen deprivation therapy is a standard-of-care treatment for metastatic prostate cancer. Paradoxically, activation of AR can also inhibit the growth of prostate cancer in some patients and experimental systems, but the mechanisms underlying this phenomenon are poorly understood. This study exploited a potent synthetic androgen, methyltestosterone (MeT), to investigate AR agonist-induced growth inhibition. MeT strongly inhibited growth of prostate cancer cells expressing AR, but not AR-negative models. Genes and pathways regulated by MeT were highly analogous to those regulated by DHT, although MeT induced a quantitatively greater androgenic response in prostate cancer cells. MeT potently downregulated DNA methyltransferases, leading to global DNA hypomethylation. These epigenomic changes were associated with dysregulation of transposable element expression, including upregulation of endogenous retrovirus (ERV) transcripts after sustained MeT treatment. Increased ERV expression led to accumulation of double-stranded RNA and a "viral mimicry" response characterized by activation of IFN signaling, upregulation of MHC class I molecules, and enhanced recognition of murine prostate cancer cells by CD8<sup>+</sup> T cells. Positive associations between AR activity and ERVs/antiviral pathways were evident in patient transcriptomic data, supporting the clinical relevance of our findings. Collectively, our study reveals that the potent androgen MeT can increase the immunogenicity of prostate cancer cells via a viral mimicry response, a finding that has potential implications for the development of strategies to sensitize this cancer type to immunotherapies.<h4>Significance</h4>Our study demonstrates that potent androgen stimulation of prostate cancer cells can elicit a viral mimicry response, resulting in enhanced IFN signaling. This finding may have implications for the development of strategies to sensitize prostate cancer to immunotherapies.
dc.description.statementofresponsibilityMohammadreza Alizadeh-Ghodsi ... Lisa M. Butler ... Theresa E. Hickey ... Wayne D. Tilley ... Luke A. Selth ... et al.
dc.identifier.citationCancer Research Communications, 2022; 2(7):706-724
dc.identifier.doi10.1158/2767-9764.crc-21-0139
dc.identifier.issn2767-9764
dc.identifier.issn2767-9764
dc.identifier.orcidGargett, T. [0000-0003-3713-1373]
dc.identifier.orcidWinter, J.M. [0000-0002-2041-8602]
dc.identifier.orcidButler, L.M. [0000-0003-2698-3220]
dc.identifier.orcidHickey, T.E. [0000-0002-2752-730X]
dc.identifier.orcidTilley, W.D. [0000-0003-1893-2626]
dc.identifier.orcidSelth, L.A. [0000-0002-4686-1418]
dc.identifier.urihttps://hdl.handle.net/2440/139145
dc.language.isoen
dc.publisherAmerican Association for Cancer Research (AACR)
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1145777
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1138242
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1156570
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/11027520
dc.rights© 2022 The Authors; Published by the American Association for Cancer Research. This open access article is distributed under the Creative Commons Attribution 4.0 International (CC BY 4.0) license.
dc.source.urihttps://doi.org/10.1158/2767-9764.crc-21-0139
dc.subjectCD8-Positive T-Lymphocytes
dc.subjectAnimals
dc.subjectHumans
dc.subjectMice
dc.subjectProstatic Neoplasms
dc.subjectAndrogen Antagonists
dc.subjectReceptors, Androgen
dc.subjectDNA
dc.subjectAndrogens
dc.subjectMale
dc.subject.meshCD8-Positive T-Lymphocytes
dc.subject.meshAnimals
dc.subject.meshHumans
dc.subject.meshMice
dc.subject.meshProstatic Neoplasms
dc.subject.meshAndrogen Antagonists
dc.subject.meshReceptors, Androgen
dc.subject.meshDNA
dc.subject.meshAndrogens
dc.subject.meshMale
dc.titlePotent Stimulation of the Androgen Receptor Instigates a Viral Mimicry Response in Prostate Cancer
dc.typeJournal article
pubs.publication-statusPublished

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