Metabolic compartmentalization and the regulation of histone propionylation in cancer

PROJECT SUMMARY Pancreatic ductal adenocarcinoma (PDA) is a deadly cancer for which effective treatments are urgently needed. Metabolism is extensively reprogrammed in pancreatic cancer to support tumor growth and progression. The epigenome is sensitive to metabolic alterations since many chromatin modifications depend on and are regulated by the abundance of key intracellular metabolites that are substrates of epigenetic enzymes. Disruption of physiological control of the metabolism-epigenome link in cancer cells has been shown to contribute to tumor growth and progression. Our labs recently identified a novel link between metabolism and the epigenome, though which branched chain amino acid (BCAA) availability and catabolism regulates histone lysine propionylation, a mark associated with transcriptional activation. Although BCAA metabolism is known to be remodeled in PDA, how this impacts chromatin modification and gene expression is unknown. Furthermore, the metabolic route through which BCAA catabolism supplies propionyl-CoA to the nucleus for chromatin modification remains unclear. This project will test the hypothesis that propionyl-CoA, the acyl-donor for histone propionylation, is generated in the nucleus of the cell via a nuclear-localized set of BCAA catabolic enzymes to regulate site-specific histone propionylation and gene expression contributing to tumor growth. We will test this hypothesis in two aims, 1) determine the mechanism of nuclear propionyl-CoA production and 2) Examine the role of BCAA-sensitive histone propionylation in gene regulation and tumor growth. Elucidation of these processes will provide insight into the mechanistic links between BCAA metabolism and PDA tumorigenesis, potentially pointing towards new avenues for therapeutic intervention.