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O-GlcNAcylation of G6PD promotes the pentose phosphate pathway and tumor growth
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O-GlcNAcylation of G6PD promotes the pentose phosphate pathway and tumor growth
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Journal Article
O-GlcNAcylation of G6PD promotes the pentose phosphate pathway and tumor growth
2015
Overview
The pentose phosphate pathway (PPP) plays a critical role in macromolecule biosynthesis and maintaining cellular redox homoeostasis in rapidly proliferating cells. Upregulation of the PPP has been shown in several types of cancer. However, how the PPP is regulated to confer a selective growth advantage on cancer cells is not well understood. Here we show that glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the PPP, is dynamically modified with an O-linked β-N-acetylglucosamine sugar in response to hypoxia. Glycosylation activates G6PD activity and increases glucose flux through the PPP, thereby providing precursors for nucleotide and lipid biosynthesis, and reducing equivalents for antioxidant defense. Blocking glycosylation of G6PD reduces cancer cell proliferation
in vitro
and impairs tumor growth
in vivo
. Importantly, G6PD glycosylation is increased in human lung cancers. Our findings reveal a mechanistic understanding of how O-glycosylation directly regulates the PPP to confer a selective growth advantage to tumours.
The pentose phosphate pathway is aberrantly activated in cancer cells but the mechanism is unclear. Here, the authors show that G6PD, the rate-limiting enzyme in the pathway, is post-translationally modified with a sugar moiety under hypoxic conditions leading to increased production of precursors for macromolecular synthesis and antioxidants.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Pub. Group
Subject
/ 692/308
/ 82/58
/ 82/80
/ Acetylglucosamine - metabolism
/ Animals
/ Cancer
/ Glucose
/ Glucose 6 phosphate dehydrogenase
/ Glucosephosphate dehydrogenase
/ Glucosephosphate Dehydrogenase - metabolism
/ Humanities and Social Sciences
/ Humans
/ Hypoxia
/ Lipids
/ Mice
/ N-Acetylglucosaminyltransferases - metabolism
/ Pentose
/ Reactive Oxygen Species - metabolism
/ Science
/ Tumors
