O-GlcNAcylation is required for mutant KRAS-induced lung tumorigenesis
Open accessAbstract
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.
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KRAS regulates these metabolic pathways through MAPK-dependent signaling, supporting survival and conferring a proliferative advantage on tumors.
“KRAS regulates these pathways through MAPK-dependent signaling cascades, ultimately supporting cell survival and conferring a proliferative advantage on tumors28,36,37.”
From The metabolic landscape of RAS-driven cancers from biology to therapy (2021) · cites this paper as [36]
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- Authors
- Taparra, K., Wang, H., Malek, R., Lafargue, A., Barbhuiya, M. A., Wang, X., Simons, B. W., Ballew, M., Nugent, K., Groves, J., Williams, R. D., Shiraishi, T., Verdone, J., Yildirir, G., Henry, R., Zhang, B., Wong, J., Wang, K. K.-H., Nelkin, B. D., Pienta, K. J., Felsher, D., Zachara, N. E., & Tran, P. T.
- Affiliations
- Sidney Kimmel Cancer Center (US)
- Johns Hopkins University (US)
- Stanford Medicine (US)
- Corresponding author
- Zachara, Natasha E.
- Tran, Phuoc T.
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2018-09-24
- Volume
- 128
- Issue
- 11
- Pages
- 4924-4937
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- PMC
- PMC6205381
- OpenAlex
- W2888685866
- Cited by
- 80
- References
- 53
- Citations by year
- 2026: 6 · 2025: 7 · 2024: 17 · 2023: 16 · 2022: 10 · 2021: 11 · 2020: 7 · 2019: 4 · 2018: 2
- FWCI
- 2.13
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI) (P01HL107153)
- National Institutes of Health (NIH) (CA199806, F31CA189588, R01CA166348)
- Mizutani Foundation for Glycoscience (Mizutani Foundation)
- Uniting Against Lung Cancer (UALC)
- Prostate Cancer Foundation (PCF)
- Nesbitt Family
- U.S. Department of Defense (DOD) (W81XWH-13-1-0182)
- Kimmel Translational Science Award (SKF-13-021)
- American Cancer Society (ACS) (122688-RSG-12-196-01-TBG)
- American Lung Association (LCD-339465)
- Movember-Prostate Cancer Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glycosylation and Glycoproteins Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA modifications and cancer
- Keywords
- O-GlcNAcylation, mutant KRAS, KRAS G12D, lung carcinogenesis, hexosamine biosynthetic pathway, epithelial-mesenchymal transition, oncogene-induced senescence, SNAI1, c-Myc, protein glycosylation, epithelial plasticity
- MeSH terms
- A549 Cells, Acylation, Animals, Cell Transformation, Neoplastic, Female, Glucose, Hexosamines, Humans, Lung Neoplasms, Mice, Nude, Mice, Transgenic, Protein Processing, Post-Translational, Proto-Oncogene Proteins p21(ras), Amino Acid Substitution, Mutation, Missense, Mice, HEK293 Cells, Epithelial-Mesenchymal Transition
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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