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

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.