Abstract 945: Novel role for SIRT1 in non-canonical activation of AR signaling

Abstract

Abstract Metastatic castrate resistance prostate cancer (CRPC) is most challenging to treat with a 5-year survival of less than 32%. Despite improved treatment landscape including use of second-generation androgen receptor (AR)-pathway inhibitors, emergence of acquired resistance is a significant problem facing both physicians and researchers. This is in part due to incomplete understanding of the compensatory molecular networks associated with therapeutic resistance. NAD+-dependent deacetylase, Sirtuin 1 (SIRT1), was traditionally known to modulate various cellular and pathological processes by regulating both histone and non-histone proteins. Furthermore, analysis of data from multiple prostate cancer cohorts indicated association of SIRT1 genetic alterations with poor clinical outcome. These findings suggest previously uncharacterized role for SIRT1 in prostate pathogenesis including therapeutic resistance. Based on these observations, we examined the role of SIRT1 in prostate pathogenesis using in vitro cell culture and in vivo preclinical models. Levels of SIRT1 are relatively higher in hormone-sensitive (LNCaP) cells compared to castrate resistant AR-positive (22Rv1) and androgen independent AR-negative (PC-3 & DU145) cells. Notably, stably knockdown (KD) of SIRT1 in LNCaP but not 22Rv1 cells showed downregulation of AR signaling pathway as evidenced by decreased levels and expression of subset of AR target genes (PSA, FKBP5), and secreted levels of PSA. Interestingly, SIRT1 KD reduced PSA reporter activity and secreted levels even under androgen depleted conditions with no significant effect on AR protein levels and nuclear translocation. Further, the observed SIRT1-mediated repression of AR signaling changes was independent of AR activation by androgen stimulation or suppression by enzalutamide. Biologically, these changes reflected in significantly decreased cell growth and migratory ability. Importantly, SIRT1 silenced LNCaP cells were more sensitive to growth suppression under conditions of androgen deprivation. Additionally, silencing of SIRT1 markedly inhibited tumor development in nude mice. Taken together, these findings led us to believe that SIRT1 could play a regulatory role in prostate pathogenesis in part by altering AR transcriptional network, independent of canonical AR signaling. Thus, our study identified previously uncharacterized role for SIRT1 in activation of AR signaling and promoting therapeutic resistance, offering avenues to develop SIRT1 or SIRT1 regulated pathways as novel therapeutic targets for PCA management. Supported by CPRIT RP150166 (APK) & CPRIT RP170345 (SH). Citation Format: Shih-Bo Huang, Dinesh Thapa, Amanda Muñoz, Roble G. Bedolla, Ratnesh Srivastav, Rita Ghosh, Addanki P. Kumar. Novel role for SIRT1 in non-canonical activation of AR signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 945.