Metabolic switch regulates lineage plasticity and induces synthetic lethality in triple-negative breast cancer.

Yingsheng Zhang, Meng-Ju Wu, Wan-Chi Lu, Yi-Chuan Li, Chun Ju Chang, Jer-Yen Yang
{"title":"Metabolic switch regulates lineage plasticity and induces synthetic lethality in triple-negative breast cancer.","authors":"Yingsheng Zhang, Meng-Ju Wu, Wan-Chi Lu, Yi-Chuan Li, Chun Ju Chang, Jer-Yen Yang","doi":"10.1016/j.cmet.2023.12.003","DOIUrl":null,"url":null,"abstract":"<p><p>Metabolic reprogramming is key for cancer development, yet the mechanism that sustains triple-negative breast cancer (TNBC) cell growth despite deficient pyruvate kinase M2 (PKM2) and tumor glycolysis remains to be determined. Here, we find that deficiency in tumor glycolysis activates a metabolic switch from glycolysis to fatty acid β-oxidation (FAO) to fuel TNBC growth. We show that, in TNBC cells, PKM2 directly interacts with histone methyltransferase EZH2 to coordinately mediate epigenetic silencing of a carnitine transporter, SLC16A9. Inhibition of PKM2 leads to impaired EZH2 recruitment to SLC16A9, and in turn de-represses SLC16A9 expression to increase intracellular carnitine influx, programming TNBC cells to an FAO-dependent and luminal-like cell state. Together, these findings reveal a new metabolic switch that drives TNBC from a metabolically heterogeneous-lineage plastic cell state to an FAO-dependent-lineage committed cell state, where dual targeting of EZH2 and FAO induces potent synthetic lethality in TNBC.</p>","PeriodicalId":93927,"journal":{"name":"Cell metabolism","volume":null,"pages":null},"PeriodicalIF":0.0000,"publicationDate":"2024-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell metabolism","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1016/j.cmet.2023.12.003","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0

Abstract

Metabolic reprogramming is key for cancer development, yet the mechanism that sustains triple-negative breast cancer (TNBC) cell growth despite deficient pyruvate kinase M2 (PKM2) and tumor glycolysis remains to be determined. Here, we find that deficiency in tumor glycolysis activates a metabolic switch from glycolysis to fatty acid β-oxidation (FAO) to fuel TNBC growth. We show that, in TNBC cells, PKM2 directly interacts with histone methyltransferase EZH2 to coordinately mediate epigenetic silencing of a carnitine transporter, SLC16A9. Inhibition of PKM2 leads to impaired EZH2 recruitment to SLC16A9, and in turn de-represses SLC16A9 expression to increase intracellular carnitine influx, programming TNBC cells to an FAO-dependent and luminal-like cell state. Together, these findings reveal a new metabolic switch that drives TNBC from a metabolically heterogeneous-lineage plastic cell state to an FAO-dependent-lineage committed cell state, where dual targeting of EZH2 and FAO induces potent synthetic lethality in TNBC.

Abstract Image

查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
代谢开关调节三阴性乳腺癌的细胞系可塑性并诱导合成致死。
代谢重编程是癌症发展的关键,然而尽管丙酮酸激酶M2(PKM2)和肿瘤糖酵解不足,三阴性乳腺癌(TNBC)细胞仍能维持生长的机制仍有待确定。在这里,我们发现肿瘤糖酵解的缺乏会激活从糖酵解到脂肪酸β-氧化(FAO)的代谢转换,从而促进 TNBC 的生长。我们发现,在 TNBC 细胞中,PKM2 直接与组蛋白甲基转移酶 EZH2 相互作用,协调介导肉碱转运体 SLC16A9 的表观遗传沉默。抑制PKM2会导致EZH2招募到SLC16A9的能力受损,进而抑制SLC16A9的表达,增加细胞内肉碱的流入,使TNBC细胞进入依赖FAO的管腔样细胞状态。这些发现共同揭示了一种新的代谢开关,它能促使 TNBC 从代谢异质性的线型可塑性细胞状态转变为 FAO 依赖性的线型承诺细胞状态,其中 EZH2 和 FAO 的双重靶向能诱导 TNBC 的强效合成致死。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 去求助
来源期刊
自引率
0.00%
发文量
0
期刊最新文献
Cytosolic calcium regulates hepatic mitochondrial oxidation, intrahepatic lipolysis, and gluconeogenesis via CAMKII activation. Obesity intensifies sex-specific interferon signaling to selectively worsen central nervous system autoimmunity in females. Serine and glycine physiology reversibly modulate retinal and peripheral nerve function. TNF compromises intestinal bile-acid tolerance dictating colitis progression and limited infliximab response. Acetate enables metabolic fitness and cognitive performance during sleep disruption.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1