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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 6

O-GlcNAcylation is sufficient and required for KrasG12D-induced lung tumorigenesis.

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O-GlcNAcylation is sufficient and required for KrasG12D-induced lung tum...
(A–C) O-GlcNAcylation was elevated pharmacologically with 1.5 mg/mL TMG in LSL mouse drinking water, and tumor burden was assessed by CT scans (A), H&E (B), and contingency table (C). The number of mice in each group was indicated. Fisher’s exact test P = 0.0439, 2-tailed. Top and bottom panels in A are representative coronal and axial sections from CT scan of the same mouse. Original magnification ×40; insets ×200 (B). (D–F) Ogt mRNA expression (D) and tumor burden via CT scan (E) at 10 weeks after intranasal administration of AdCre in Ogt knockout mice (n = 3 without AdCre, n = 3 with AdCre). (F) Tumor-free survival Kaplan-Meier curves of LSL mice (median 8 weeks post-AdCre) compared with CS-LSL (median 2 weeks), elevated O-GlcNAcylation mice (LSL-TMG median 5 weeks), and Ogt knockout mice (LSL-Ogt–/Y median 15 weeks). The number of mice in each group is indicated. Error bars indicate mean ± SD. Unless stated, P values were derived from unpaired, 2-tailed Student’s t test in D, and log-rank test in F. **P < 0.01, ****P < 0.0001.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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