ALDH1A3-acetaldehyde metabolism potentiates transcriptional heterogeneity in melanoma
Cancer cell heterogeneity and resistance to therapy are largely driven by metabolic and transcriptional adaptations, yet the connection between these processes remains unclear. In this study, we demonstrate that in melanoma, the cancer stem cell marker ALDH1A3 partners with acetyl-CoA synthetase 2 (ACSS2) within the nucleus to link high glucose metabolism with acetylation of histone H3 at genes involved in neural crest (NC) lineage and glucose metabolism. Notably, we identify acetaldehyde as a metabolic source for histone H3 acetylation in an ALDH1A3-dependent manner, revealing a physiological role for this typically toxic and volatile metabolite.
Using a zebrafish model of melanoma residual disease, we show that a subpopulation of ALDH1-high cells persists following BRAF inhibitor treatment. Targeting these cells with the ALDH1 suicide inhibitor nifuroxazide significantly delays or prevents the development of resistance to BRAF inhibitors. This work uncovers a direct link between nuclear acetaldehyde-acetyl-CoA metabolism and gene regulation, mediated by the ALDH1A3–ACSS2 complex,ACSS2 inhibitor and highlights a potential therapeutic vulnerability in melanoma.