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

Author

Listed:
  • Zihao Guo

    (Capital Medical University
    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
    Capital Medical University
    Tianjin Medical University Cancer Institute and Hospital)

  • Chuanzhen Yang

    (Capital Medical University
    Westlake Laboratory of Life Sciences and Biomedicine)

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.

Suggested Citation

  • Zihao Guo & Yang Zhang & Haoyue Wang & Liming Liao & Lingdi Ma & Yiliang Zhao & Ronghui Yang & Xuexue Li & Jing Niu & Qiaoyun Chu & Yanxia Fu & Binghui Li & Chuanzhen Yang, 2024. "Hypoxia-induced downregulation of PGK1 crotonylation promotes tumorigenesis by coordinating glycolysis and the TCA cycle," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-51232-w
    DOI: 10.1038/s41467-024-51232-w
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    References listed on IDEAS

    as
    1. Rachel Fellows & Jérémy Denizot & Claudia Stellato & Alessandro Cuomo & Payal Jain & Elena Stoyanova & Szabina Balázsi & Zoltán Hajnády & Anke Liebert & Juri Kazakevych & Hector Blackburn & Renan Oliv, 2018. "Microbiota derived short chain fatty acids promote histone crotonylation in the colon through histone deacetylases," Nature Communications, Nature, vol. 9(1), pages 1-15, December.
    2. Yapeng Ji & Chuanzhen Yang & Zefang Tang & Yongfeng Yang & Yonglu Tian & Hongwei Yao & Xi Zhu & Zemin Zhang & Jiafu Ji & Xiaofeng Zheng, 2017. "Adenylate kinase hCINAP determines self-renewal of colorectal cancer stem cells by facilitating LDHA phosphorylation," Nature Communications, Nature, vol. 8(1), pages 1-16, August.
    3. Hao Nie & Haixing Ju & Jiayi Fan & Xiaoliu Shi & Yaxian Cheng & Xiaohui Cang & Zhiguo Zheng & Xiaotao Duan & Wen Yi, 2020. "O-GlcNAcylation of PGK1 coordinates glycolysis and TCA cycle to promote tumor growth," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    4. Shiwen Wang & Bowen Jiang & Tengfei Zhang & Lixia Liu & Yi Wang & Yiping Wang & Xiufei Chen & Huaipeng Lin & Lisha Zhou & Yukun Xia & Leilei Chen & Chen Yang & Yue Xiong & Dan Ye & Kun-Liang Guan, 2015. "Insulin and mTOR Pathway Regulate HDAC3-Mediated Deacetylation and Activation of PGK1," PLOS Biology, Public Library of Science, vol. 13(9), pages 1-27, September.
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