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

Signal Transduction and Targeted Therapy

Article

Danna Yeerken¹  Di Yang¹  Dongshao Chen¹  Xuesong Liu¹  Qingjie Min¹  Jinting Li¹  Xianfeng Li¹  Mengzhu Lv¹  Rui Liu¹  Ying Gong²  Qingnan Wu³  Jie Chen³  Yan Wang³  Weimin Zhang⁴  Qimin Zhan⁵  Dongyu Zhao⁶ 

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

关键词: ;   

DOI  :  10.1038/s41392-023-01555-9

 received in 2022-12-06, accepted in 2023-06-28,  发布年份 2023

来源: Springer

【 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.

【 授权许可】

CC BY   
© West China Hospital, Sichuan University 2023

【 图 表 】

40854_2023_500_Article_IEq6.gif

Fig. 3

12888_2023_5124_Article_IEq1.gif

13690_2023_1147_Article_IEq8.gif

Fig. 1

Fig. 4