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.
摘要：
癌细胞异质性和治疗抗性主要来自代谢和转录适应。但是人们对它们之间的联系知之甚少。这里,我们证明，在黑色素瘤中，癌症干细胞标记醛脱氢酶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，以将高葡萄糖代谢通量与神经c（NC）谱系和葡萄糖代谢基因的乙酰组蛋白H3修饰偶联。重要的是,我们表明乙醛是乙酰组蛋白H3修饰的代谢物来源，为这种高挥发性和毒性的代谢物提供生理功能。在斑马鱼黑色素瘤残留病模型中，BRAF抑制剂治疗后出现ALDH1高亚群，用ALDH1自杀抑制剂靶向这些药物，硝呋嗪,延迟或防止BRAF抑制剂耐药复发。我们的工作表明，ALDH1A3-ACSS2偶联直接协调核乙醛-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。
