Abstract A019: Epigenetic regulation by H3K9 methylation enables resistance to anti-androgen therapy in prostate cancer

Abstract Prostate cancer (PCa) is a major cause of cancer mortality in the United States. Androgen receptor (AR) is the key transcriptional regulator for the development and progression of prostate cancer. Androgen deprivation therapy (ADT) with medical castration and treatment with second-generation anti-androgens such as enzalutamide and abiraterone acetate are important treatments for advanced prostate cancer. Previous studies have shown resistance to enzalutamide develops through various alternative molecular mechanisms including AR gene amplification, mutations in the ligand binding domains of AR, and increased expression of glucocorticoid receptor (GR). Recent reports further indicate that resistance to enzalutamide is accompanied with various de novo genomic and transcriptional changes that lead to reduced AR activity and acquisition of stem-cell like properties along with increased expression of genes associated with epithelial-to-mesenchymal transition and inflammatory signaling pathway, including interleukin 6 (IL6), janus kinase-signal transducer and activator of transcription (JAK-STAT) and interferon (IFN). In our study, we have unraveled a novel mechanism of epigenetic regulation mediated by H3K9 methylation in response to anti-androgen treatment in PCa cells. We have shown enzalutamide treatment leads to aberrant activation of endogenous retroelements (REs) which causes accumulation of double stranded RNA (dsRNA) in the PCa cells. This results in an antiviral response mediated via IFN signaling and induction of apoptosis, a phenomenon known as viral mimicry. Using a forward genetic screen, we have identified that the epigenetic machinery associated with H3K9 methylation is responsible for suppressing the aberrant transcription of REs in response to anti-androgen treatment. Further, overexpression of the terminal H3K9me3 writers lead to the suppression of REs whereas pharmacological or genetic inhibition of H3K9 trimethylation writers and readers restored REs expression, abrogating resistance to anti-androgen. Moreover, elevated expression of terminal H3K9me3 writers is associated with poor outcomes in patients subjected to hormonal therapy. Interestingly, we have observed that inhibition of double-stranded RNA-specific adenosine deaminase (ADAR1) leads to accumulation of dsRNA and modulates GR expression in PCa cells. Taken together, our study highlights the role of H3K9 trimethylation in mediating resistance to anti-androgen therapy in prostate cancer. Notably, members of the H3K9 trimethylation machinery could potentially serve as therapeutic targets and combinatorial approaches targeting epigenetic regulatory enzymes as well as androgen signaling axis could be a promising strategy for overcoming drug resistance and immune evasion in prostate cancer. Citation Format: Ritika Tiwari, Mehdi Baratchian, Michael Berk, Jianneng Li, Amy Guerinot, Vladimir Makarov, Timothy A. Chan, Abhishek A. Chakraborty, Nima Sharifi. Epigenetic regulation by H3K9 methylation enables resistance to anti-androgen therapy in prostate cancer. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr A019.