Abstract 4706: Transcriptional repression of mitochondrial deacetylase SIRT3 promotes prostate cancer metastasis

Abstract

Abstract Prostate cancer (PCa) is the most common cancer and the second leading cause of cancer death among men in America. Aggressive prostate tumors that rapidly metastasize to other organs such as bones account for high morbidity and mortality. Metastatic PCa is resistant to androgen depletion therapy, and increased expression of androgen receptor (AR) coregulator Steroid Receptor Coregulator-2 (SRC-2) remains a major underlying driver of lethal PCa progression. Increased expression of SRC-2 positively correlates with PCa recurrence and poor disease outcome. SRC-2 directly binds to AR and regulates its transcriptional activity even in castrate-levels of androgen. Although the role of SRC-2 as a coactivator of AR is well established, we recently discovered that SRC-2 can also function as a co-repressor of AR on certain gene promoters such as mitochondrial deacetylase Sirtuin 3 (SIRT3). Analysis of human PCa databases revealed that expression of SIRT3 is reduced in prostate tumors as the disease progresses to metastatic PCa, and there exists an inverse correlation with SRC-2 expression. To confirm that SRC-2 is functioning as a co-repressor on SIRT3 promoter we performed chromatin immunoprecipitation (ChIP) and identified strong occupancy of SRC-2 on the SIRT3 promoter along with AR, whereas SRC-2 knockdown reduced AR enrichment. Consistently with this observation SRC-2 or AR knockdown significantly increased SIRT3 expression in PCa lines C4-2 and 22RV1, validating that SRC-2 functions as a transcriptional co-repressor of AR on SIRT3 promoter. This suggests that AR/SRC-2 can transcriptionally silence potential tumor suppressors. Next, we investigated the role of SIRT3 in PCa, and adenovirus-mediated ectopic expression of SIRT3 significantly impaired cell cycle progression arresting TRAMP-C2 and C4-2 cells in G0/G1 phase with reduced cell growth and viability, suggesting SIRT3 may function as a tumor suppressor in PCa. Since SRC-2 represses SIRT3 gene expression we analyzed mRNA expression of SRC-2 and SIRT3 in metastatic lesions from human prostate cancer patients using an advanced prostate cancer genomics dataset. We found that increased levels of SRC-2 with a concomitant reduction in SIRT3 expression is prevalent in metastatic lesions of PCa patients that spread to bones and lymph nodes. We used intra-iliac artery (IIA) injection to selectively deliver C4-2 cells expressing stable knockdown of SRC-2 (shSRC-2) or NTshRNA into the hind limb tissues. After 12 weeks we found SRC-2 ablation almost completely abolished PCa colonization in the bone whereas all animals transplanted with C4-2-NTshRNA developed bone metastasis. In conclusion, our study indicates that transcriptional repression of tumor suppressor SIRT3 by SRC2 may function as an oncogenic driver of lethal PCa progression to the bone. This work is supported by DoD grant: W81XWH-16-1-0297, NCI grant: K22CA207578 and Roswell Park Alliance Foundation. Citation Format: Mayrel Palestino Dominguez, Abhisha Sawant Dessai, Eriko Katsuta, Tao Dai, Subhamoy Dasgupta. Transcriptional repression of mitochondrial deacetylase SIRT3 promotes prostate cancer metastasis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4706.