PUBLICATION

ALDH1A3-acetaldehyde metabolism potentiates transcriptional heterogeneity in melanoma

Authors
Lu, Y., Travnickova, J., Badonyi, M., Rambow, F., Coates, A., Khan, Z., Marques, J., Murphy, L.C., Garcia-Martinez, P., Marais, R., Louphrasitthiphol, P., Chan, A.H.Y., Schofield, C.J., von Kriegsheim, A., Marsh, J.A., Pavet, V., Sansom, O.J., Illingworth, R.S., Patton, E.E.
ID
ZDB-PUB-240705-4
Date
2024
Source
Cell Reports   43: 114406114406 (Journal)
Registered Authors
Patton, E. Elizabeth
Keywords
ACSS2, ALDH1A3, CP: Cancer, CP: Metabolism, Nifuroxazide, TFAP2B, acetaldehyde, melanoma, neural crest stem cell, pyruvate metabolism, residual disease
MeSH Terms
  • Coenzyme A Ligases/genetics
  • Coenzyme A Ligases/metabolism
  • Transcription, Genetic/drug effects
  • Melanoma*/drug therapy
  • Melanoma*/genetics
  • Melanoma*/metabolism
  • Melanoma*/pathology
  • Histones/metabolism
  • Acetaldehyde*/metabolism
  • Acetaldehyde*/pharmacology
  • Cell Line, Tumor
  • Animals
  • Gene Expression Regulation, Neoplastic/drug effects
  • Aldehyde Oxidoreductases/genetics
  • Aldehyde Oxidoreductases/metabolism
  • Zebrafish*
  • Humans
  • Neural Crest/drug effects
  • Neural Crest/metabolism
(all 19)
PubMed
38963759 Full text @ Cell Rep.
Abstract
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.
Genes / Markers
Figures
Figure Gallery (7 images)
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Expression
No data available
Phenotype
No data available
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
czt13TgTransgenic Insertion
    w47TgTransgenic Insertion
      zdf1
        		Point Mutation
        1 - 3 of 3
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        Human Disease / Model
        No data available
        Sequence Targeting Reagents
        No data available
        Fish
        No data available
        Antibodies
        No data available
        Orthology
        No data available
        Engineered Foreign Genes
        Marker Marker Type Name
        GFPEFGGFP
        1 - 1 of 1
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        Mapping
        No data available
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        Citation
        Lu, Y., Travnickova, J., Badonyi, M., Rambow, F., Coates, A., Khan, Z., Marques, J., Murphy, L.C., Garcia-Martinez, P., Marais, R., Louphrasitthiphol, P., Chan, A.H.Y., Schofield, C.J., von Kriegsheim, A., Marsh, J.A., Pavet, V., Sansom, O.J., Illingworth, R.S., Patton, E.E. (2024) ALDH1A3-acetaldehyde metabolism potentiates transcriptional heterogeneity in melanoma. Cell Reports. 43:114406114406.