2. Academic Validation
  3. O-GlcNAcylation Facilitates the Interaction between Keratin 18 and Isocitrate Dehydrogenases and Potentially Influencing Cholangiocarcinoma Progression

O-GlcNAcylation Facilitates the Interaction between Keratin 18 and Isocitrate Dehydrogenases and Potentially Influencing Cholangiocarcinoma Progression

  • ACS Cent Sci. 2024 Apr 23;10(5):1065-1083. doi: 10.1021/acscentsci.4c00163.
Xiangfeng Meng 1,  Yue Zhou 2,  Lei Xu 2,  Limu Hu 1,  Changjiang Wang 1,  Xiao Tian 1,  Xiang Zhang 2,  Yi Hao 3,  Bo Cheng 4,  Jing Ma 1 5,  Lei Wang 2,  Jialin Liu 6,  Ran Xie 1 7 8
Affiliations

Affiliations

  • 1 State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023, China.
  • 2 Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated, Hospital of Nanjing University Medical School, Nanjing 210008, China.
  • 3 College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China.
  • 4 School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
  • 5 Collaborative Innovation Center of Advanced Microstructures, Nanjing University, Nanjing 210023, China.
  • 6 State Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 102206, China.
  • 7 Chemistry and Biomedicine Innovation Center (ChemBIC), Nanjing University, Nanjing 210023, China.
  • 8 Beijing National Laboratory for Molecular Sciences, Beijing 100191, China.
PMID: 38799671 DOI: 10.1021/acscentsci.4c00163
Abstract

Glycosylation plays a pivotal role in the intricate landscape of human cholangiocarcinoma (CCA), actively participating in key pathophysiological processes driving tumor progression. Among the various glycosylation modifications, O-linked β-N-acetyl-glucosamine modification (O-GlcNAcylation) emerges as a dynamic regulator influencing diverse tumor-associated biological activities. In this study, we employed a state-of-the-art chemical proteomic approach to analyze intact glycopeptides, unveiling the critical role of O-GlcNAcylation in orchestrating Keratin 18 (K18) and its interplay with tricarboxylic acid (TCA) cycle Enzymes, specifically isocitrate dehydrogenases (IDHs), to propel CCA progression. Our findings shed light on the mechanistic intricacies of O-GlcNAcylation, revealing that site-specific modification of K18 on Ser 30 serves as a stabilizing factor, amplifying the expression of cell cycle checkpoints. This molecular event intricately fosters cell cycle progression and augments cellular growth in CCA. Notably, the interaction between O-GlcNAcylated K18 and IDHs orchestrates metabolic reprogramming by down-regulating citrate and isocitrate levels while elevating α-ketoglutarate (α-KG). These metabolic shifts further contribute to the overall tumorigenic potential of CCA. Our study thus expands the current understanding of protein O-GlcNAcylation and introduces a new layer of complexity to post-translational control over metabolism and tumorigenesis.

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