静止是一种可逆的细胞周期退出，传统上被认为与代谢不活跃状态有关。最近对肌肉细胞的研究表明，代谢重编程与静止有关。癌症中是否发生代谢变化以驱动静止尚不清楚。使用多组学方法，我们发现将乙酸盐转化为乙酰辅酶A的代谢酶ACSS2在静止卵巢癌细胞中高度上调，并且是其生存所必需的。事实上，静止的卵巢癌细胞中乙酸衍生的乙酰辅酶A的水平增加，证实了这些细胞中ACSS2活性的增加。此外，诱导 ACSS2 表达或向细胞补充乙酸盐足以诱导可逆的静止细胞周期退出。醋酸盐处理细胞的 RNA-Seq 证实了多个细胞周期途径的负富集以及已发表的 G0 基因特征中的基因富集。最后，对患者数据的分析表明，腹水中的肿瘤细胞中 ACSS2 表达上调，与匹配的原发肿瘤相比，腹水肿瘤细胞被认为更加静止。此外，ACSS2 高表达与铂耐药和更差的结果相关。总之，这项研究指出了一种以前未被认识到的 ACSS2 介导的代谢重编程，它导致卵巢癌的静止。由于治疗卵巢癌的化疗（例如铂）在高度增殖的细胞中提高了疗效，我们的数据提出了一个有趣的问题，即代谢驱动的静止可能会影响治疗反应。版权所有 © 2024 作者。由 Elsevier GmbH 出版。保留所有权利。

Quiescence is a reversible cell cycle exit traditionally thought to be associated with a metabolically inactive state. Recent work in muscle cells indicates that metabolic reprogramming is associated with quiescence. Whether metabolic changes occur in cancer to drive quiescence is unclear. Using a multi-omics approach, we found that the metabolic enzyme ACSS2, which converts acetate into acetyl-CoA, is both highly upregulated in quiescent ovarian cancer cells and required for their survival. Indeed, quiescent ovarian cancer cells have increased levels of acetate-derived acetyl-CoA, confirming increased ACSS2 activity in these cells. Furthermore, either inducing ACSS2 expression or supplementing cells with acetate was sufficient to induce a reversible quiescent cell cycle exit. RNA-Seq of acetate treated cells confirmed negative enrichment in multiple cell cycle pathways as well as enrichment of genes in a published G0 gene signature. Finally, analysis of patient data showed that ACSS2 expression is upregulated in tumor cells from ascites, which are thought to be more quiescent, compared to matched primary tumors. Additionally, high ACSS2 expression is associated with platinum resistance and worse outcomes. Together, this study points to a previously unrecognized ACSS2-mediated metabolic reprogramming that drives quiescence in ovarian cancer. As chemotherapies to treat ovarian cancer, such as platinum, have increased efficacy in highly proliferative cells, our data give rise to the intriguing question that metabolically-driven quiescence may affect therapeutic response.Copyright © 2024 The Author(s). Published by Elsevier GmbH.. All rights reserved.