乙酸通过ACSS2介导的乙酰辅酶A生成驱动卵巢癌静止状态

Acetate drives ovarian cancer quiescence via ACSS2-mediated acetyl-CoA production

Molecular Metabolism

影响因子:6.6

分区:医学2区 Top / 内分泌学与代谢2区

发表日期:2024 Nov

作者: Allison C Sharrow, Emily Megill, Amanda J Chen, Afifa Farooqi, Naveen Kumar Tangudu, Apoorva Uboveja, Stacy McGonigal, Nadine Hempel, Nathaniel W Snyder, Ronald J Buckanovich, Katherine M Aird

DOI: 10.1016/j.molmet.2024.102031

摘要

静止状态被认为是一种可逆的细胞周期退出，传统上与代谢活性低的状态相关。肌肉细胞的最新研究表明，代谢重编程与静止状态有关。是否在癌症中也存在代谢变化以驱动静止，尚不清楚。采用多组学方法，我们发现代谢酶ACSS2（乙酸转化为乙酰辅酶A）在静止的卵巢癌细胞中高度上调，且对其存活至关重要。实际上，静止卵巢癌细胞中乙酸衍生的乙酰辅酶A水平升高，证实了ACSS2活性的增强。此外，诱导ACSS2表达或补充乙酸即可引发可逆的细胞周期静止退出。对乙酸处理细胞的RNA-Seq分析确认多个细胞周期相关通路的负富集，以及已发表的G0基因签名中的基因富集。最后，患者数据分析显示，腹水中的肿瘤细胞（被认为更倾向于静止）中ACSS2表达上调，与匹配的原发肿瘤相比。此外，高ACSS2表达与铂类耐药和预后不良相关。综上，该研究揭示了一种先前未被认识的由ACSS2介导的代谢重编程，驱动卵巢癌的静止状态。鉴于对卵巢癌的化疗药物（如铂类）在高度增殖细胞中效果更佳，我们的研究引发了一个有趣的问题：代谢驱动的静止状态可能影响治疗反应。

Abstract

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.