Abstract 3798: Branched-chain amino acid metabolism and histone propionylation in pancreatic cancer

Abstract Pancreatic ductal adenocarcinoma (PDA) is a deadly cancer for which development of effective therapies is urgently needed. Metabolic programs are vastly remodeled in pancreatic cancer to favor the production of certain metabolites that support tumor progression. Previous studies reported that catabolism of branched-chain amino acids (BCAAs) is the major carbon source for energy production in healthy pancreatic acinar cells. However, in PDA cells, BCAA metabolism is reprogrammed and its contribution to the TCA cycle is suppressed. Our labs recently showed that BCAAs, primarily isoleucine, are a primary supplier of propionyl-CoA (pr-CoA), which accumulates in the nuclei of cancer cells and is utilized for site-specific histone lysine propionylation (Kpr). Yet, the metabolic route through which BCAA catabolism supplies pr-CoA to the nucleus, as well as the distinct function of BCAA-derived Kpr in promoting tumor growth, are currently unknown. Here, we find that disrupting BCAA catabolism in PDA cells by either nutrient deprivation or genetic manipulation significantly decreases pr-CoA pools and the global levels of selective Kpr marks. Loss of BCAA-derived Kpr downregulates the expression of specific genes associated with lipid metabolism and immunosuppression. Accordingly, defective BCAA oxidation inhibits PDA tumor growth in vitro and in vivo, signifying the potential of targeting BCAA metabolism to attenuate PDA progression. Remarkably, we show that, in addition to their expected location in the mitochondria, BCAA metabolic enzymes also are detectable in the nuclear compartment of PDA cells and primary patient tissues, suggesting on-site synthesis of pr-CoA for Kpr. Overall, our findings support a novel link between metabolism and epigenetics in which segregation of a nuclear specific BCAA metabolic sub-network is harnessed by PDA cells to boost histone propionylation and shape malignant gene expression signatures. Citation Format: Christina Demetriadou, Michael Noji, Erick Mitchell-Velasquez, Sharan Venkatesh, Austin Good, Taku Harada, Daniel Kantner, Zoltan Arany, Irfan Asangani, Ben Stanger, Nathaniel Snyder, Kathryn Wellen. Branched-chain amino acid metabolism and histone propionylation in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3798.