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

  • Signal Transduct Target Ther. 2023 Aug 16;8(1):302. doi: 10.1038/s41392-023-01555-9.
Mengzhu Lv  #  1 ,  Ying Gong  #  1  2 ,  Xuesong Liu  #  1 ,  Yan Wang  1  3 ,  Qingnan Wu  1  3 ,  Jie Chen  1  3 ,  Qingjie Min  1 ,  Dongyu Zhao  4 ,  Xianfeng Li  1 ,  Dongshao Chen  1 ,  Di Yang  1 ,  Danna Yeerken  1 ,  Rui Liu  1 ,  Jinting Li  1 ,  Weimin Zhang  5  6  7  8 ,  Qimin Zhan  9  10  11  12  13
Affiliations
  • 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. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Molecular Oncology, Peking University Cancer Hospital and Institute, Beijing, 100142, China. [email protected].
  • 6. Research Unit of Molecular Cancer Research, Chinese Academy of Medical Sciences, Beijing, 100021, China. [email protected].
  • 7. Institute of Cancer Research, Shenzhen Bay Laboratory, Shenzhen, 518107, China. [email protected].
  • 8. 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. [email protected].
  • 9. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Molecular Oncology, Peking University Cancer Hospital and Institute, Beijing, 100142, China. [email protected].
  • 10. Research Unit of Molecular Cancer Research, Chinese Academy of Medical Sciences, Beijing, 100021, China. [email protected].
  • 11. Peking University International Cancer Institute, Beijing, 100191, China. [email protected].
  • 12. Institute of Cancer Research, Shenzhen Bay Laboratory, Shenzhen, 518107, China. [email protected].
  • 13. Soochow University Cancer Institute, Suzhou, 215127, China. [email protected].
  • # Contributed equally.
PMID: 37582812 DOI: 10.1038/s41392-023-01555-9
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.

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