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
  • 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. [email protected].
  • 5. Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China. [email protected].
  • 6. Department of Cancer Cell Biology and National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China. [email protected].
  • 7. Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China. [email protected].
  • 8. Westlake Four-Dimensional Dynamic Metabolomics (Meta4D) Laboratory, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, 310024, China. [email protected].
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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