ALDH1A3-acetaldehyde metabolism potentiates transcriptionalheterogeneity in melanoma

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-CoA synthetase 2 (ACSS2) in the nucleus to couple high glucose metabolic flux with acetyl-histone H3 modification of neural crest lineage and glucose metabolism genes. Importantly, we show 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 model of melanoma residual disease, a subpopulation of ALDH1-high cells 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. HighlightsO_LIALDH1A3-high melanomas are in a high glucose metabolic flux and neural crest stem cell dual state. C_LIO_LINuclear ALDH1A3 partners with ACSS2 to promote selective acetyl-histone H3. C_LIO_LIAcetaldehyde is an acetyl source for ALDH1A3 dependent histone H3 acetylation. C_LIO_LIALDH1A3 is a master regulator and pharmaceutical target for melanoma heterogeneity. C_LI