A nuclear branched-chain amino acid catabolism pathway controls histone propionylation in pancreatic cancer.

ABSTRACT: Branched-chain amino acid (BCAA) catabolism contributes prominently to the TCA cycle in the healthy pancreas but is suppressed in pancreatic ductal adenocarcinoma (PDA). The impact of this metabolic remodeling on cancer phenotypes remains poorly understood. Here, we find that the BCAA isoleucine is a primary source of propionyl-CoA in PDA cells. Reduction of propionyl-CoA availability by either genetic perturbation or isoleucine and valine starvation decreases histone propionylation (Kpr) without impacting histone acetylation on specific lysine sites, correlating with reduced transcription of certain lipid- and immune-related genes. Mechanistically, we find that multiple enzymes of isoleucine catabolism unexpectedly localize to and carry out multi-step isoleucine oxidation within the nucle

SUBMITTER: Demetriadou C 

PROVIDER: S-EPMC12191106 | biostudies-literature | 2025 Apr

REPOSITORIES: biostudies-literature