CDK7-YAP-LDHD axis promotes D-lactate elimination and ferroptosis defense to support cancer stem cell-like properties

查看全文 作　　者：Mengzhu [1]Lv;Ying [1,2]Gong;Xuesong [1]Liu;Yan [1,3]Wang;Qingnan [1,3]Wu;Jie [1,3]Chen;Qingjie [1]Min;Dongyu [4]Zhao;Xianfeng [1]Li;Dongshao [1]Chen;Di [1]Yang;Danna [1]Yeerken;Rui [1]Liu;Jinting [1]Li;Weimin [1,3,5,6]Zhang;Qimin [1,3,4,5,7]Zhan

机构地区：[1]Key Laboratory of Carcinogenesis and Translational Research(Ministry of Education),Department of Molecular Oncology,Peking University Cancer Hospital and Institute,Beijing 100142,China;[2]Key Laboratory of Carcinogenesis and Translational Research(Ministry of Education),Department of Breast Oncology,Peking University Cancer Hospital and Institute,Beijing 100142,China;[3]Research Unit of Molecular Cancer Research,Chinese Academy of Medical Sciences,Beijing 100021,China;[4]Peking University International Cancer Institute,Beijing 100191,China;[5]Institute of Cancer Research,Shenzhen Bay Laboratory,Shenzhen 518107,China;[6]Department of Oncology,Cancer Institute,Peking University Shenzhen Hospital,Shenzhen Peking University-Hong Kong University of Science and Technology(PKU-HKUST)Medical Center,Shenzhen 518036,China;[7]Soochow University Cancer Institute,Suzhou 215127,China

出　　处：《Signal Transduction and Targeted Therapy》索引2023年第8卷第9期,共19页

基　　金：This work was supported by the National Natural Science Foundation of China(81988101,82172930,81830086,and 81802780);Beijing Municipal Commission of Health and Family Planning Project(PXM2018_026279_000005);Beijing Nova Program(Z191100001119038);CAMS Innovation Fund for Medical Sciences(2019-I2M-5-081);Funding by Major Program of Shenzhen Bay Laboratory(S201101004);Guangdong Basic and Applied Basic Research Foundation(2019B030302012);the Fund of“San-ming”Project of Medicine in Shenzhen(No.SZSM201812088);Suzhou Outstanding Talent Team Fund(ZXD2022003). 摘　　要：Reprogrammed cellular metabolism is essential for maintaining cancer stem cells(CSCs)state.Here,we report that mitochondrial D-lactate catabolism is a necessary initiating oncogenic event during tumorigenesis of esophageal squamous cell carcinoma(ESCC).We discover that cyclin-dependent kinase 7(CDK7)phosphorylates nuclear Yes-associated protein 1(YAP)at S127 and S397 sites and enhances its transcription function,which promotes D-lactate dehydrogenase(LDHD)protein expression.Moreover,LDHD is enriched significantly in ESCC-CSCs rather than differentiated tumor cells and high LDHD status is connected with poor prognosis in ESCC patients.Mechanistically,the CDK7-YAP-LDHD axis helps ESCC-CSCs escape from ferroptosis induced by D-lactate and generates pyruvate to satisfy energetic demands for their elevated self-renewal potential.Hence,we conclude that esophageal CSCs adopt a D-lactate elimination and pyruvate accumulation mode dependent on CDK7-YAP-LDHD axis,which drives stemness-associated hallmarks of ESCC-CSCs.Reasonably,targeting metabolic checkpoints may serve as an effective strategy for ESCC therapy. 关键词：ESOPHAGEAL metabolism ELEVATED

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CDK7-YAP-LDHD axis promotes D-lactate elimination and ferroptosis defense to support cancer stem cell-like properties

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