A Metabolic-Epigenetic Mechanism Directs Cell Fate and Therapeutic Sensitivity in Breast Cancer.
A Metabolic-Epigenetic Mechanism Directs Cell Fate and Therapeutic Sensitivity in Breast Cancer.
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代谢表观遗传机制指导乳腺癌的细胞命运和治疗敏感性。
DOI：
10.1158/0008-5472.can-24-0460
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发表时间：
2024
期刊：
影响因子：
11.2
通讯作者：
Goldstein,AndrewS
中科院分区：
文献类型：
--
作者：
Bernard,MatthewJ;Goldstein,AndrewS
在过去的十年里，研究越来越多地揭示了细胞代谢和细胞命运之间的相互关系，这意味着细胞的谱系既驱动又受其特定代谢特征的支配。Zhang及其同事最近发表在《细胞代谢》杂志上的一项研究描述了一种新的代谢-表观遗传调控轴，它控制着三阴性乳腺癌（TNBC）的谱系身份。在主要发现中，作者证明代谢酶丙酮酸激酶M2 （PKM2）直接与细胞核中zeste同源物2的组蛋白甲基转移酶增强子（EZH2）结合，以沉默包括线粒体肉碱转运体slc16a9在内的一组基因的表达。这种代谢-表观遗传调控机制的扰动诱导代谢从糖酵解转向脂肪酸氧化。随后的肉毒碱的涌入促进了激活表观遗传标记H3K27Ac沉积到gata3的启动子上，驱动了一个承诺的管腔血统状态。重要的是，这种代谢-表观遗传轴代表了TNBC治疗的潜在靶向脆弱性，TNBC是一种目前缺乏有效治疗策略的亚型。这些发现进一步支持了我们对癌症代谢理解的范式转变：细胞燃料源的功能不仅提供能量，而且指导细胞命运的表观遗传调控。
Over the past decade, studies have increasingly shed light on a reciprocal relationship between cellular metabolism and cell fate, meaning that a cell's lineage both drives and is governed by its specific metabolic features. A recent study by Zhang and colleagues, published inCell Metabolism, describes a novel metabolic–epigenetic regulatory axis that governs lineage identity in triple-negative breast cancer (TNBC). Among the key findings, the authors demonstrate that the metabolic enzyme pyruvate kinase M2 (PKM2) directly binds to the histone methyltransferase enhancer of zeste homolog 2 (EZH2) in the nucleus to silence expression of a set of genes that includes the mitochondrial carnitine transporterSLC16A9. Perturbation of this metabolic–epigenetic regulatory mechanism induces a metabolic shift away from glycolysis and toward fatty acid oxidation. The ensuing influx of carnitine facilitates the deposition of the activating epigenetic mark H3K27Ac onto the promoter ofGATA3, driving a committed luminal lineage state. Importantly, this metabolic–epigenetic axis represents a potentially targetable vulnerability for the treatment of TNBC, a subtype that currently lacks effective therapeutic strategies. These findings lend further support for the paradigm shift underlying our understanding of cancer metabolism: that a cellular fuel source functions not only to provide energy but also to direct the epigenetic regulation of cell fate.