Publication in Nature Chemical Biology by Prof. ZHOU Ruhong's Laboratory & YI Wen's Laboratory

Title: O-GlcNAcylation promotes pancreatic tumor growth by regulating malate dehydrogenase 1

Qiang Zhu, Hong Zhou, Liming Wu, Zhenyuan Lai, Didi Geng, Weiwei Yang, Jie Zhang, Zhiya Fan, Weijie Qin, Yong Wang, Ruhong Zhou & Wen Yi

Published: 25 July 2022

Abstract

Oncogenic Kras-activated pancreatic ductal adenocarcinoma (PDAC) cells highly rely on an unconventional glutamine catabolic pathway to sustain cell growth. However, little is known about how this pathway is regulated. Here we demonstrate that Kras mutation induces cellular O-linked β-N-acetylglucosamine (O-GlcNAc), a prevalent form of protein glycosylation. Malate dehydrogenase 1 (MDH1), a key enzyme in the glutamine catabolic pathway, is positively regulated by O-GlcNAcylation on serine 189 (S189). Molecular dynamics simulations suggest that S189 glycosylation on monomeric MDH1 enhances the stability of the substrate-binding pocket and strengthens the substrate interactions by serving as a molecular glue. Depletion of O-GlcNAcylation reduces MDH1 activity, impairs glutamine metabolism, sensitizes PDAC cells to oxidative stress, decreases cell proliferation and inhibits tumor growth in nude mice. Furthermore, O-GlcNAcylation levels of MDH1 are elevated in clinical PDAC samples. Our study reveals that O-GlcNAcylation contributes to pancreatic cancer growth by regulating the metabolic activity of MDH1.

Link:  https://www.nature.com/articles/s41589-022-01085-5

    

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