Affiliation:
1. Nanjing University
2. Nanjing Drum Tower Hospital, The Affiliated, Hospital of Nanjing University Medical School
3. The Affiliated Drum Tower Hospital of Nanjing University Medical School
4. Peking University
5. National Center for Protein Sciences (Beijing)
Abstract
Abstract
Glycosylation in human cholangiocarcinoma (CCA) actively contributes to pathophysiological steps of tumor progression. Of note is the dynamic modification of proteins by O-linked β-N-acetyl-glucosamine (O-GlcNAcylation) that modulates various tumor-associated biological activities. By using a cutting-edge chemical proteomic methodology for intact glycopeptide analysis, we show herein that O-GlcNAcylation of Keratin 18 (K18) coordinates the tricarboxylic acid (TCA) cycle enzymes, namely isocitrate dehydrogenases (IDHs), to promote CCA progression. Mechanistically, site-specific O-GlcNAcylation of K18 on Ser 30 stabilizes K18, which benefits the expression of cell cycle checkpoints to enhance cell cycle progression and cell growth. Interaction with IDHs down-regulates the level of citrate and isocitrate, while up-regulates the level of α-ketoglutarate (α-KG). Our study thus expands the current understanding of protein O-GlcNAcylation, and adds another dimension of complexity to post-translational control over metabolism and tumorigenesis.
Publisher
Research Square Platform LLC
Reference62 articles.
1. Cholangiocarcinoma 2020: the next horizon in mechanisms and management;Banales JM;Nat Rev Gastroenterol Hepatol.,2020
2. Cholangiocarcinoma-evolving concepts and therapeutic strategies;Rizvi S;Nat Rev Clin Oncol.,2018
3. Worldwide incidence and mortality of biliary tract cancer;Baria K;Gastro Hep Adv.,2022
4. Varki A, Cummings RD, Esko JD, Stanley P, Hart GW, Aebi M, et al. Essentials of glycobiology. 4th edn. Ch. 46–47 (Cold Spring Harbor Laboratory Press, 2022).
5. Glycosylation in cancer: mechanisms and clinical implications;Pinho SS;Nat Rev Cancer,2015