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

Nat Chem Biol. 2022 Oct;18(10):1087-1095. doi: 10.1038/s41589-022-01085-5.

Qiang Zhu ^# ¹, Hong Zhou ^# ¹ ², Liming Wu ³, Zhenyuan Lai ¹, Didi Geng ¹, Weiwei Yang ¹, Jie Zhang ⁴, Zhiya Fan ⁵, Weijie Qin ⁵, Yong Wang ¹ ² ⁶, Ruhong Zhou ⁷ ⁸ ⁹ ¹⁰, Wen Yi ¹¹ ¹² ¹³

Affiliations

1 Ministry of Education Key Laboratory of Biosystems Homeostasis & Protection, College of Life Sciences, Zhejiang University, Hangzhou, China.
2 Shanghai Institute for Advanced Study, Institute of Quantitative Biology, Zhejiang University, Hangzhou, China.
3 Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang Provincial Key Laboratory of Pancreatic Disease, School of Medicine, Zhejiang University, Hangzhou, China.
4 Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jiaxing, The Affiliated Hospital of Jiaxing University, Jiaxing, China.
5 National Center for Protein Sciences Beijing, State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Lifeomics, Beijing, China.
6 The Provincial International Science and Technology Cooperation Base on Engineering Biology, International Campus of Zhejiang University, Haining, China.
7 Ministry of Education Key Laboratory of Biosystems Homeostasis & Protection, College of Life Sciences, Zhejiang University, Hangzhou, China. [email protected].
8 Shanghai Institute for Advanced Study, Institute of Quantitative Biology, Zhejiang University, Hangzhou, China. [email protected].
9 Department of Chemistry, Columbia University, New York, NY, USA. [email protected].
10 Cancer Center, Zhejiang University, Hangzhou, China. [email protected].
11 Ministry of Education Key Laboratory of Biosystems Homeostasis & Protection, College of Life Sciences, Zhejiang University, Hangzhou, China. [email protected].
12 Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang Provincial Key Laboratory of Pancreatic Disease, School of Medicine, Zhejiang University, Hangzhou, China. [email protected].
13 Cancer Center, Zhejiang University, Hangzhou, China. [email protected].
# Contributed equally.

PMID: 35879546 DOI: 10.1038/s41589-022-01085-5

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.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-12588

Thiamet G

99.98%, O-GlcNAcase Inhibitor

Autophagy

Cancer

Name
Email *

	Sorry, but the email address you supplied was invalid.