Abstract 4741: Loss of SIRT3 promotes metabolic and epigenetic dysregulation in aggressive prostate cancer

Abstract Prostate cancer is one of the leading causes of cancer-related deaths among men worldwide. Localized prostate tumors in certain patients relapse after surgery, radiation therapy or androgen deprivation therapy (ADT), leading to an aggressive metastatic recurrent disease. We recently found that in prostate cancer patients, SIRT3 (sirtuin 3) expression is significantly decreased in advanced metastatic disease compared to localized tumors. SIRT3 is a mitochondrial deacetylase that modulates the biochemical functions of its substrates by regulating their acetylation status. Restoration of SIRT3 levels in human and mouse prostate tumors reduced prostate cancer progression in both immune-deficient and immune competent animals. Transcriptomic profiling and targeted metabolomics analysis of bulk tumors revealed that SIRT3 regulates one-carbon metabolism pathway by controlling the levels of s-adenosyl methionine (SAM) pools. Mechanistic studies indicated that SIRT3 interacts with the rate limiting enzymes MAT1A and MAT2A that catalyze the conversion of methionine to SAM. Biochemical experiments indicated that SIRT3 deacetylates MAT1A/MAT2A which may contribute towards increased SAM synthesis. Additionally, we found that restoration of SIRT3 levels in prostate tumors increased macrophage reprogramming in the tumor microenvironment of the syngeneic mouse models. These findings provide rationale for our working hypothesis that SIRT3 may modulate prostate tumor-immune microenvironment by regulating one-carbon metabolism, and its loss accelerates lethal prostate cancer progression. Supported by NCI grants: R01CA285707 and R01CA252092 to S.D. Citation Format: Xiaochen Yu, Alphonse Nicholas Dimeck, Eriko Katsuta, Spencer Rosario, Mark Long, Song Liu, Kent Nastiuk, Hai Wang, Subhamoy Dasgupta. Loss of SIRT3 promotes metabolic and epigenetic dysregulation in aggressive prostate cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4741.