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
-
- Acetaldehyde*/metabolism
- Acetaldehyde*/pharmacology
- Aldehyde Oxidoreductases/genetics
- Aldehyde Oxidoreductases/metabolism
- Animals
- Cell Line, Tumor
- Coenzyme A Ligases/genetics
- Coenzyme A Ligases/metabolism
- Gene Expression Regulation, Neoplastic/drug effects
- Histones/metabolism
- Humans
- Melanoma*/drug therapy
- Melanoma*/genetics
- Melanoma*/metabolism
- Melanoma*/pathology
- Neural Crest/drug effects
- Neural Crest/metabolism
- Transcription, Genetic/drug effects
- Zebrafish*
- PubMed
- 38963759 Full text @ Cell Rep.
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.
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
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping