异柠檬酸脱氢酶
化学
计算生物学
角蛋白
计算机科学
生物化学
生物
癌症研究
酶
遗传学
作者
Xianna Meng,Yifei Zhou,Xu Liu,Lei Hu,Changjing Wang,Xiao Tian,Xiang Zhang,Yi Hao,Bo Cheng,Jing Ma,Jing Ma,Lei Wang,Jialin Liu,Ran Xie,Ran Xie,Ran Xie
出处
期刊:ACS central science
[American Chemical Society]
日期:2024-04-23
标识
DOI:10.1021/acscentsci.4c00163
摘要
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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