A nuclear branched-chain amino acid catabolism pathway controls histone propionylation and transcription in pancreatic cancer
Branched-chain amino acid (BCAA) catabolism is a major contributor to the TCA cycle in the healthy pancreas but is suppressed in pancreatic ductal adenocarcinoma (PDA). The impact of this metabolic remodeling on the epigenome remains poorly understood. Here, we identify the BCAA isoleucine as the primary contributor to propionyl-CoA pools across PDA cell lines. Reduction of propionyl-CoA availability by either genetic perturbation or isoleucine and valine starvation decreases histone propionylation (Kpr) on specific lysine sites, correlating with reduced transcription of certain lipid- and immune-related genes. We further show that isoleucine-sensitive Kpr and its associated gene expression are tightly regulated by the MYST family of lysine acyltransferases (KATs). Mechanistically, we find that isoleucine oxidation occurs within the nuclei of PDA cells and that nuclear localization of the rate-limiting branched-chain alpha ketoacid dehydrogenenase (BCKDH) complex is essential for isoleucine-dependent Kpr and gene regulation. Moreover, we demonstrate that the BCKDHA subunit interacts with the KAT HBO1 within the nuclear compartment. Notably, BCKDH is apparent in the nuclei of PanIN lesions in mice and PDA tumors in patients, contrasting that in healthy pancreatic acinar and ductal cells. Collectively, these findings unveil a nuclear BCAA catabolism pathway and highlight its role in controlling histone Kpr and tumorigenic transcriptional programs in PDA.