Non-Canonical Activation Of Ar Signaling By Histone Deacetylase Sirt1

SIRT1, a nicotinamide adenine dinucleotide (NAD)-dependent deacetylase, is a member of multigene family of Sirtuins. Traditionally SIRT1 is a known player in enhancing longevity. SIRT1 can target both histone and non-histone proteins to regulate diverse activities including cellular stress resistance, genomic stability, energy metabolism and tumorigenesis. Disruption of SIRT1 in the prostate results in the formation of prostatic intraepithelial neoplasia (PIN) lesions, suggesting a role for SIRT1 in the development of PIN, a precursor lesion for prostate cancer (PCA). Paradoxically, an oncogenic role for SIRT1 was reported as evidenced by development of micro-invasive prostate carcinomas in Pten +/- /Sirt1tg mice. Therefore, SIRT1 may possess both oncogenic and tumor suppressor activities in a context-dependent manner and its role in human cancer remains controversial. To address these paradoxical findings, we examined the role of SIRT1 in prostate pathogenesis using stably silenced for SIRT1 prostate cancer cell lines. Silencing SIRT1 in androgen responsive LNCaP cells resulted in (i) morphological changes indicative of clustering and epithelial mesenchymal transition (EMT); (ii) significant reduction in their ability to form colonies on soft agar; and (iii) increased autophagic flux. Similarly, silencing SIRT1 resulted in reduced proliferative, colony forming and migratory ability of androgen independent PC-3 cells. Furthermore, notably, genes involved in nuclear receptor (PXR/RXR/FXR/PPAR) and kinase (AMPK, MSP-RON, and RhoA) signaling are significantly altered as evidenced by RNA-seq analysis in these cells. Remarkably, SIRT1 KD cells showed decreased expression of AR and its target genes including PSA, TMPRSS-2, FKBP-5 and PMEPA1. Interestingly, SIRT1 KD reduced PSA-luciferase activity under both normal physiological and androgen deprivation growth conditions with no significant effect on nuclear or cytosolic levels of AR. More importantly, SIRT1 KD cells showed increased sensitivity to growth under androgen deprivation conditions. Intervention with resveratrol (RES, known SIRT1 activator) reduced incidence of HGPIN in prostate specific PTEN KO mouse model with no significant differences in the expression of AR or SIRT1. Consistent with these in vivo observations, SIRT1 had no significant impact on RES-induced growth inhibition. Taken together, these data indicate that SIRT1 could potentially contribute to androgen independence, independent of classical AR signaling. Our study demonstrates that SIRT1 may not play an essential role in mediating RES-induced tumor growth inhibition and that SIRT1 may confer resistance to androgen deprivation therapy and sustains cell survival, suggesting that combination of SIRT1 inhibitors and ADT might be a potential strategy for advanced PCA treatment. Supported by CPRIT RP 150166 and NCI CA 137518 (APK). Citation Format: Shih-Bo Huang, Dinesh Thapa, Suleman S. Hussain, Roble G. Bedolla, Guiming Li, Robert L. Reddick, Zhao Lai, Hung-I H. Chen, Yidong Chen, Rita Ghosh, Addanki P. Kumar. Non-canonical activation of AR signaling by histone deacetylase SIRT1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3521. doi:10.1158/1538-7445.AM2017-3521