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J Clin Invest. 2018 Nov 1;128(11):4924-4937. doi: 10.1172/JCI94844. Epub 2018 Sep 24.

O-GlcNAcylation is required for mutant KRAS-induced lung tumorigenesis.

Author information

1
Department of Radiation Oncology and Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center.
2
Program in Cellular and Molecular Medicine.
3
Department of Urology, James Buchanan Brady Urological Institute.
4
Department of Biological Chemistry, and.
5
Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
6
Division of Medical Oncology, Departments of Medicine and Pathology, Stanford University School of Medicine, Stanford, California, USA.

Abstract

Mutant KRAS drives glycolytic flux in lung cancer, potentially impacting aberrant protein glycosylation. Recent evidence suggests aberrant KRAS drives flux of glucose into the hexosamine biosynthetic pathway (HBP). HBP is required for various glycosylation processes, such as protein N- or O-glycosylation and glycolipid synthesis. However, its function during tumorigenesis is poorly understood. One contributor and proposed target of KRAS-driven cancers is a developmentally conserved epithelial plasticity program called epithelial-mesenchymal transition (EMT). Here we showed in novel autochthonous mouse models that EMT accelerated KrasG12D lung tumorigenesis by upregulating expression of key enzymes of the HBP pathway. We demonstrated that HBP was required for suppressing KrasG12D-induced senescence, and targeting HBP significantly delayed KrasG12D lung tumorigenesis. To explore the mechanism, we investigated protein glycosylation downstream of HBP and found elevated levels of O-linked β-N-acetylglucosamine (O-GlcNAcylation) posttranslational modification on intracellular proteins. O-GlcNAcylation suppressed KrasG12D oncogene-induced senescence (OIS) and accelerated lung tumorigenesis. Conversely, loss of O-GlcNAcylation delayed lung tumorigenesis. O-GlcNAcylation of proteins SNAI1 and c-MYC correlated with the EMT-HBP axis and accelerated lung tumorigenesis. Our results demonstrated that O-GlcNAcylation was sufficient and required to accelerate KrasG12D lung tumorigenesis in vivo, which was reinforced by epithelial plasticity programs.

KEYWORDS:

Cancer; Cellular senescence; Glycobiology; Oncology

PMID:
30130254
PMCID:
PMC6205381
DOI:
10.1172/JCI94844
[Indexed for MEDLINE]
Free PMC Article

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