High Glucose Triggers Nucleotide Imbalance through O-GlcNAcylation of Key Enzymes and Induces KRAS Mutation in Pancreatic Cells
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KRAS mutations are the earliest events found in approximately 90% of pancreatic ductal adenocarcinomas (PDACs). However, little is known as to why KRAS mutations preferentially occur in PDACs and what processes/factors generate these mutations. While abnormal carbohydrate metabolism is associated with a high risk of pancreatic cancer, it remains elusive whether a direct relationship between KRAS mutations and sugar metabolism exists. Here, we show that under high-glucose conditions, cellular O-GlcNAcylation is significantly elevated in pancreatic cells that exhibit lower phosphofructokinase (PFK) activity than other cell types. This post-translational modification specifically compromises the ribonucleotide reductase (RNR) activity, leading to deficiency in dNTP pools, genomic DNA alterations with KRAS mutations, and cellular transformation. These results establish a mechanistic link between a perturbed sugar metabolism and genomic instability that induces de novo oncogenic KRAS mutations preferentially in pancreatic cells.
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Diabetes increases the frequency of KRAS variants in human pancreas, possibly through chronic hyperglycemia effects on nucleotide balance.
“Diabetes increases the frequency of KRAS variants in human pancreas, possibly through the effects of chronic hyperglycemia on nucleotide balance (17).”
From Metabolic reprogramming and cancer progression (2020) · cites this paper as [17]
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- Authors
- Hu, C.-M., Tien, S.-C., Hsieh, P.-K., Jeng, Y.-M., Chang, M.-C., Chang, Y.-T., Chen, Y.-J., Chen, Y.-J., Lee, E. Y.-H. P., & Lee, W.-H.
- Affiliations
- Genomics Research Center, Academia Sinica (TW)
- National Taiwan University Hospital (TW)
- Institute of Chemistry, Academia Sinica (TW)
- University of California, Irvine (US)
- China Medical University (TW)
- Corresponding author
- Hu, Chun-Mei
- Lee, Wen-Hwa
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2019-06
- Volume
- 29
- Issue
- 6
- Pages
- 1334-1349.e10
- ISSN
- 1550-4131 (ISSN-L)
- OpenAlex
- W2922490226
- Cited by
- 123
- References
- 61
- Citations by year
- 2026: 12 · 2025: 16 · 2024: 17 · 2023: 18 · 2022: 15 · 2021: 23 · 2020: 12 · 2019: 10
- FWCI
- 6.26
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- Ministry of Science and Technology, Taiwan (104-0210-01-09-02, 105-0210-01-13-01, 106-0210-01-15-02)
- Academia Sinica
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- 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
- Keywords
- high glucose, O-GlcNAcylation, KRAS mutation, pancreatic ductal adenocarcinoma, phosphofructokinase, ribonucleotide reductase, dNTP pools, genomic instability, sugar metabolism, post-translational modification, pancreatic cells, cell transformation
- MeSH terms
- Acetylation, Acetylglucosamine, Acetyltransferases, Adult, Aged, Animals, Cell Transformation, Neoplastic, Cells, Cultured, DNA Damage, Dose-Response Relationship, Drug, Enzymes, Female, Glucose, Humans, Infant, Newborn, Male, Mice, Inbred C57BL, Middle Aged, Mutation, Nucleotides, Pancreas, Pancreatic Neoplasms, Protein Processing, Post-Translational, Proto-Oncogene Proteins p21(ras), Mutagenesis, Carcinoma, Pancreatic Ductal, Mice, Metabolic Networks and Pathways, Young Adult, HEK293 Cells
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