癌细胞异质性和治疗耐药性很大程度上是由代谢和转录适应引起的，但人们对它们之间的相互关系知之甚少。在这里，我们发现，在黑色素瘤中，癌症干细胞标记物乙醛脱氢酶 1A3 (ALDH1A3) 与细胞核中的乙酰辅酶 A (CoA) 合成酶 2 (ACSS2) 形成酶促伙伴关系，将高葡萄糖代谢通量与乙酰组蛋白结合起来神经嵴 (NC) 谱系和葡萄糖代谢基因的 H3 修饰。重要的是，我们证明乙醛是以 ALDH1A3 依赖性方式进行乙酰组蛋白 H3 修饰的代谢物来源，为这种高度挥发性和有毒的代谢物提供了生理功能。在斑马鱼黑色素瘤残留病模型中，BRAF 抑制剂治疗后会出现 ALDH1 高亚群，使用 ALDH1 自杀抑制剂硝呋嗪可延缓或预防 BRAF 抑制剂耐药性复发。我们的工作揭示了 ALDH1A3-ACSS2 对直接协调核乙醛-乙酰-CoA 代谢与特定的基于染色质的基因调控，并代表了黑色素瘤的潜在治疗脆弱性。版权所有 © 2024 作者。由爱思唯尔公司出版。保留所有权利。

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.Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.