1. CDK7-YAP-LDHD axis promotes D-lactate elimination and ferroptosis defense to support cancer stem cell-like properties
- Author
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Lv, Mengzhu, Gong, Ying, Liu, Xuesong, Wang, Yan, Wu, Qingnan, Chen, Jie, Min, Qingjie, Zhao, Dongyu, Li, Xianfeng, Chen, Dongshao, Yang, Di, Yeerken, Danna, Liu, Rui, Li, Jinting, Zhang, Weimin, Zhan, Qimin, Lv, Mengzhu, Gong, Ying, Liu, Xuesong, Wang, Yan, Wu, Qingnan, Chen, Jie, Min, Qingjie, Zhao, Dongyu, Li, Xianfeng, Chen, Dongshao, Yang, Di, Yeerken, Danna, Liu, Rui, Li, Jinting, Zhang, Weimin, and Zhan, Qimin
- Abstract
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.
- Published
- 2023