Abstract 539: Pro-proliferative function of the histone deacetylase SIRT3 in prostate cancer

Worldwide, prostate cancer (PCa) is the second most frequently diagnosed cancer and fifth leading cause of cancer death in males. The existing treatments, as well as surgical approaches, have not been fully effective either for prevention or treatment of PCa. This necessitates a need to intensify our efforts towards the understanding of genetics and mechanism(s) of PCa. This may lead to the identification of the novel molecular target(s) and mechanism-based approaches for the management of this neoplasm. Sirtuin-3 (SIRT3) is a nicotinamide adenine dinucleotide (NAD)-dependent deacetylase primarily located in the mitochondria and known to play important roles in the regulation of a variety of cellular processes, including transcription and programmed cell death. The fact that SIRT3 can regulate several cellular processes those are critical in cancer cell proliferation, makes it a potential therapeutic target for cancer management. Moreover, SIRT3 is a central regulator of mitochondrial adaptive responses that relate to metabolic reprogramming of cancer cells. However, the role of SIRT3 in cancer, including PCa, is not well understood and it has been shown to act both as a tumor suppressor as well as a tumor promoter. In this study, we determined the role of SIRT3 in PCa, employing in vitro and ex vivo approaches. The first step in our efforts to understand the role of SIRT3 in PCa was to check the expression profile of SIRT3 in a panel of human PCa cell line (DU145, 22Rν1, PC3, LNCaP, C4-2, MDA PCa 2b, E006AA-Par and E006AA-hT) by RT-qPCR and immunoblot analyses. Compared to normal human prostate epithelial cells (NrPEC), PCa cells showed higher expression of SIRT3, both at mRNA and protein levels. Further, we determined the expression profile of SIRT3 by immunostaining of a tissue microarray (TMA) containing paraffin-embedded sections of 40 cases of prostate adenocarcinoma and 8 normal prostate tissues. Our data demonstrated a significant upregulation of SIRT3 in cancerous prostatic tissues compared to the normal tissues. We next determined the effect of chemical inhibition of SIRT3 using a recently described SIRT3 inhibitor viz. 49-Bromo-Resveratrol (4BR), in human PCa cells (DU145 and 22Rν1). 4BR treatment at 10, 20 and 40 μM concentrations for 48 and 72 h resulted in a dose- and time-dependent decrease in cell growth and proliferation. Further, 4BR treatment resulted in a marked decrease in clonogenic survival of DU145 and 22Rν1 PCa cells. Furthermore, 4BR treatment resulted in a marked cleavage of PARP, an indicator of apoptosis induction; and a decrease in the level of PCNA, a marker of cellular proliferation, in human PCa cells. Overall, our data suggest a possible pro-proliferative function of SIRT3 in PCa. Further studies are underway to unravel the role and functional significance of SIRT3 during PCa development and progression. Citation Format: Chandra K. Singh, Gagan Chhabra, Minakshi Nihal, Kenneth A. Iczkowski, Nihal Ahmad. Pro-proliferative function of the histone deacetylase SIRT3 in prostate cancer [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 539.