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

Zihao Guo, Yang Zhang, Haoyue Wang, Liming Liao, Lingdi Ma, Yiliang Zhao, Ronghui Yang, Xuexue Li, Jing Niu, Qiaoyun Chu, Yanxia Fu, Binghui Li () and Chuanzhen Yang ()
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Zihao Guo: Capital Medical University
Yang Zhang: Capital Medical University
Haoyue Wang: Capital Medical University
Liming Liao: Westlake Laboratory of Life Sciences and Biomedicine
Lingdi Ma: Capital Medical University
Yiliang Zhao: Capital Medical University
Ronghui Yang: Capital Medical University
Xuexue Li: Capital Medical University
Jing Niu: Capital Medical University
Qiaoyun Chu: Capital Medical University
Yanxia Fu: Capital Medical University
Binghui Li: Capital Medical University
Chuanzhen Yang: Capital Medical University

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-51232-w

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