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bioRxiv · 10.1101/2023.07.23.550247

O-GlcNAcylation of Keratin 18 coordinates TCA cycle to promote cholangiocarcinoma progression

Xie, R.·Liu, J.·Wang, L.·Meng, X.·Zhou, Y.·Xu, L.·Wang, C.·Tian, X.·Zhang, X.·Hao, Y.·Cheng, B.
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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 {beta}-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 -ketoglutarate (-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.

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Xie, R., Liu, J., Wang, L., Meng, X., Zhou, Y., Xu, L., Wang, C., Tian, X., Zhang, X., Hao, Y., Cheng, B.. 2023-07-25. O-GlcNAcylation of Keratin 18 coordinates TCA cycle to promote cholangiocarcinoma progression. https://doi.org/10.1101/2023.07.23.550247

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