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O-GlcNAcylation is required for mutant KRAS-induced lung tumorigenesis
Kekoa Taparra, … , Natasha E. Zachara, Phuoc T. Tran
Kekoa Taparra, … , Natasha E. Zachara, Phuoc T. Tran
Published August 21, 2018
Citation Information: J Clin Invest. 2018;128(11):4924-4937. https://doi.org/10.1172/JCI94844.
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Research Article Oncology Article has an altmetric score of 2

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

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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.

Authors

Kekoa Taparra, Hailun Wang, Reem Malek, Audrey Lafargue, Mustafa A. Barbhuiya, Xing Wang, Brian W. Simons, Matthew Ballew, Katriana Nugent, Jennifer Groves, Russell D. Williams, Takumi Shiraishi, James Verdone, Gokben Yildirir, Roger Henry, Bin Zhang, John Wong, Ken Kang-Hsin Wang, Barry D. Nelkin, Kenneth J. Pienta, Dean Felsher, Natasha E. Zachara, Phuoc T. Tran

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Figure 5

O-GlcNAcylation is required to suppress senescence.

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O-GlcNAcylation is required to suppress senescence.
(A) Schematic of UDP...
(A) Schematic of UDP-GlcNAc incorporation into N-linked and O-linked glycosylation with inhibitors (red). (B) Nucleotide sugar analysis with reversed-phase HPLC in several lung cancer cell lines overexpressing TWIST1 led to increased levels of O-HexNAc. Aggregate UDP-HexNAc level in A549, H460 and H358 cells with or without TWIST1 overexpression. Experiment was repeated 3 times. P = 0.0313, 2-sided Welch t test. (C) OGT protein level in A549 cells with overexpression of SNAI1. (D) Ogt mRNA level and (E and F) OGT protein levels by Western blot in lung tumor tissues from CR, CRS, and CRT mice (CR: n = 5, CRS: n = 6, CRT: n = 7 mice, same samples and actin/Snai1/Twist1 blot membrane as in Figure 2, D and E). (G and H) Global O-GlcNAcylation of proteins by Western blot in lung tumor tissues from CR, CRS, and CRT mice (CR: n = 5, CRS: n = 6, CRT: n = 7 mice). (I) SA-βGal staining following 48-hour attenuation of O-GlcNAcylation via overexpression of OGA. (J) SA-βGal staining following pharmacological inhibition of N-glycosylation (TUNI) compared with OGT inhibition (TT04). (K) SA-βGal staining of TT04-treated NSCLC cell lines. More than 500 cells were counted for SA-βGal quantification in each experiment. Data are representative of 3 independent experiments. Original magnification ×400. Error bars indicate mean ± SD. Unless stated, P values were derived from an unpaired, 2-tailed Student’s t test in B, G, H, and I; 1-way ANOVA and Dunnett’s multiple comparisons test were performed in D and J; 2-way ANOVA and Sidak’s multiple comparisons test were performed in K. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.

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