2. Academic Validation
  3. Hypoxia-induced downregulation of PGK1 crotonylation promotes tumorigenesis by coordinating glycolysis and the TCA cycle

Hypoxia-induced downregulation of PGK1 crotonylation promotes tumorigenesis by coordinating glycolysis and the TCA cycle

  • Nat Commun. 2024 Aug 12;15(1):6915. doi: 10.1038/s41467-024-51232-w.
Zihao Guo 1 2,  Yang Zhang 1,  Haoyue Wang 1,  Liming Liao 3,  Lingdi Ma 1,  Yiliang Zhao 2,  Ronghui Yang 1,  Xuexue Li 1,  Jing Niu 2,  Qiaoyun Chu 2,  Yanxia Fu 2,  Binghui Li 4 5 6,  Chuanzhen Yang 7 8
Affiliations

Affiliations

  • 1 Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, 100069, China.
  • 2 Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China.
  • 3 Westlake Four-Dimensional Dynamic Metabolomics (Meta4D) Laboratory, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, 310024, China.
  • 4 Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, 100069, China. bli@ccmu.edu.cn.
  • 5 Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China. bli@ccmu.edu.cn.
  • 6 Department of Cancer Cell Biology and National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China. bli@ccmu.edu.cn.
  • 7 Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China. yangchuanzhen@westlake.edu.cn.
  • 8 Westlake Four-Dimensional Dynamic Metabolomics (Meta4D) Laboratory, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, 310024, China. yangchuanzhen@westlake.edu.cn.
PMID: 39134530 DOI: 10.1038/s41467-024-51232-w
Abstract

Protein post-translational modifications (PTMs) are crucial for Cancer cells to adapt to hypoxia; however, the functional significance of lysine crotonylation (Kcr) in hypoxia remains unclear. Herein we report a quantitative proteomics analysis of global crotonylome under normoxia and hypoxia, and demonstrate 128 Kcr site alterations across 101 proteins in MDA-MB231 cells. Specifically, we observe a significant decrease in K131cr, K156cr and K220cr of phosphoglycerate kinase 1 (PGK1) upon hypoxia. Enoyl-CoA hydratase 1 (ECHS1) is upregulated and interacts with PGK1, leading to the downregulation of PGK1 Kcr under hypoxia. Abolishment of PGK1 Kcr promotes glycolysis and suppresses mitochondrial pyruvate metabolism by activating pyruvate dehydrogenase kinase 1 (PDHK1). A low PGK1 K131cr level is correlated with malignancy and poor prognosis of breast Cancer. Our findings show that PGK1 Kcr is a signal in coordinating glycolysis and the tricarboxylic acid (TCA) cycle and may serve as a diagnostic indicator for breast Cancer.

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