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

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

  • bioRxiv. 2025 Apr 26:2025.04.23.650241. doi: 10.1101/2025.04.23.650241.
Christina Demetriadou 1 2 3 4,  Michael Noji 1 2 3 5,  Austin L Good 2 5 6,  Erick Mitchell-Velasquez 1 2 3,  Sharan Venkatesh 1 2 3,  Daniel S Kantner 4,  Jennifer Pennise 1 2 3,  Pedro Costa-Pinheiro 1 2 3,  Laura V Pinheiro 1 2 3,  Taku Harada 1 2,  Phuong T T Nguyen 1 2 3,  Adam Chatoff 4,  Emily Megill 4,  Claudia V Da Silva Crispim 4,  Mariola M Marcinkiewicz 4,  Jordan L Meier 7,  Zoltan Arany 5,  Irfan Asangani 1 2,  Emma E Furth 6,  Ben Z Stanger 2 5,  Nathaniel W Snyder 4,  Kathryn E Wellen 1 2 3
Affiliations

Affiliations

  • 1 Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA, USA.
  • 2 Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, USA.
  • 3 Penn Epigenetics Institute, University of Pennsylvania, Philadelphia, PA, USA.
  • 4 Aging + Cardiovascular Discovery Center, Department of Cardiovascular Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA.
  • 5 Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 6 Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 7 Chemical Biology Laboratory, National Cancer Institute, Bethesda, Maryland, USA.
PMID: 40568091 DOI: 10.1101/2025.04.23.650241
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 nuclei of PDA cells. Importantly, nuclear localization of the rate-limiting branched-chain alpha ketoacid dehydrogenase (BCKDH) complex is essential for isoleucine-dependent Kpr and gene regulation. Moreover, we demonstrate that isoleucine-sensitive Kpr and its associated gene expression are driven by the MYST family of lysine acyltransferases (KATs), and that the BCKDHA subunit of the BCKDH complex interacts with KAT7 within the nuclear compartment. BCAA catabolism Enzymes are 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 isoleucine catabolism pathway and highlight its role in controlling histone Kpr and tumorigenic transcriptional programs in PDA.

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