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

• Published in: Nature communications Vol. 15; no. 1; pp. 6915 - 17
• Main Authors: Guo, Zihao, Zhang, Yang, Wang, Haoyue, Liao, Liming, Ma, Lingdi, Zhao, Yiliang, Yang, Ronghui, Li, Xuexue, Niu, Jing, Chu, Qiaoyun, Fu, Yanxia, Li, Binghui, Yang, Chuanzhen
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 12.08.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 13/109; 13/31; 13/51; 14/19; 38/1; 631/67/2327; 631/80/86; 64/60; 82/16; 82/58; 82/80; 96/95; Animals; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Carcinogenesis - genetics; Carcinogenesis - metabolism; Cell Hypoxia; Cell Line, Tumor; Citric Acid Cycle; Cycle protein; Down-Regulation; Enoyl-CoA hydratase; Female; Gene Expression Regulation, Neoplastic; Glycolysis; Glycolysis - genetics; Humanities and Social Sciences; Humans; Hypoxia; Kinases; Lysine; Lysine - metabolism; Malignancy; Metabolism; Mice; Mice, Nude; Mitochondria - metabolism; multidisciplinary; Phosphoglycerate kinase; Phosphoglycerate Kinase - genetics; Phosphoglycerate Kinase - metabolism; Phosphoglycerate kinase 1; Post-translation; Protein Processing, Post-Translational; Proteins; Proteomics; Proteomics - methods; Pyruvate Dehydrogenase Acetyl-Transferring Kinase - genetics; Pyruvate Dehydrogenase Acetyl-Transferring Kinase - metabolism; Pyruvic acid; Science; Science (multidisciplinary); Tricarboxylic acid cycle; Tumorigenesis
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-51232-w

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. The functional relevance of lysine crotonylation in cancer remains to be further explored. Here, the authors show that hypoxia-induced downregulation of PGK1 lysine crotonylation promotes glycolysis and suppresses mitochondrial pyruvate metabolism, contributing to breast cancer progression.