ALDH1A3-acetaldehyde metabolism potentiates transcriptional heterogeneity in melanoma

Yuting Lu, Jana Travnickova, Mihaly Badonyi, Florian Rambow, Andrea Coates, Zaid Khan, Jair Marques Junior, Laura C. Murphy, Pablo Garcia-Martinez, Richard Marais, Pakavarin Louphrasitthiphol, Alex H.Y. Chan, Christopher J. Schofield, Alex von Kriegsheim, Joseph A. Marsh, Valeria Pavet, Owen J. Sansom, Robert S. Illingworth, E. Elizabeth Patton*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

Cancer cellular heterogeneity and therapy resistance arise substantially from metabolic and transcriptional adaptations, but how these are interconnected is poorly understood. Here, we show that, in melanoma, the cancer stem cell marker aldehyde dehydrogenase 1A3 (ALDH1A3) forms an enzymatic partnership with acetyl-coenzyme A (CoA) synthetase 2 (ACSS2) in the nucleus to couple high glucose metabolic flux with acetyl-histone H3 modification of neural crest (NC) lineage and glucose metabolism genes. Importantly, we show that acetaldehyde is a metabolite source for acetyl-histone H3 modification in an ALDH1A3-dependent manner, providing a physiologic function for this highly volatile and toxic metabolite. In a zebrafish melanoma residual disease model, an ALDH1-high subpopulation emerges following BRAF inhibitor treatment, and targeting these with an ALDH1 suicide inhibitor, nifuroxazide, delays or prevents BRAF inhibitor drug-resistant relapse. Our work reveals that the ALDH1A3-ACSS2 couple directly coordinates nuclear acetaldehyde-acetyl-CoA metabolism with specific chromatin-based gene regulation and represents a potential therapeutic vulnerability in melanoma.

Original languageEnglish
Article number114406
JournalCell Reports
Volume43
Issue number7
DOIs
Publication statusPublished - 3 Jul 2024

Keywords / Materials (for Non-textual outputs)

  • acetaldehyde
  • ACSS2
  • ALDH1A3
  • CP: Cancer
  • CP: Metabolism
  • melanoma
  • neural crest stem cell
  • Nifuroxazide
  • pyruvate metabolism
  • residual disease
  • TFAP2B

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