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

作　　者：Mengzhu Lv Ying Gong Xuesong Liu Yan Wang Qingnan Wu Jie Chen Qingjie Min Dongyu Zhao Xianfeng Li Dongshao Chen Di Yang Danna Yeerken Rui Liu Jinting Li Weimin Zhang Qimin 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》2023年第9期4346-4364,共19页信号转导与靶向治疗（英文）

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 

分 类 号：R730[医药卫生—肿瘤]