High Glucose Triggers Nucleotide Imbalance through O-GlcNAcylation of Key Enzymes and Induces KRAS Mutation in Pancreatic Cells

Chun-Mei Hu; Sui-Chih Tien; Ping-Kun Hsieh; Yung-Ming Jeng; Ming-Chu Chang; Yu-Ting Chang; Yi-Ju Chen; Yu-Ju Chen; Eva Y-H P Lee; Wen-Hwa Lee

doi:10.1016/j.cmet.2019.02.005

High Glucose Triggers Nucleotide Imbalance through O-GlcNAcylation of Key Enzymes and Induces KRAS Mutation in Pancreatic Cells

Cell Metab. 2019 Jun 4;29(6):1334-1349.e10. doi: 10.1016/j.cmet.2019.02.005. Epub 2019 Mar 7.

Authors

Chun-Mei Hu¹, Sui-Chih Tien², Ping-Kun Hsieh², Yung-Ming Jeng³, Ming-Chu Chang⁴, Yu-Ting Chang⁴, Yi-Ju Chen⁵, Yu-Ju Chen⁵, Eva Y-H P Lee⁶, Wen-Hwa Lee⁷

Affiliations

¹ Genomics Research Center, Academia Sinica, Taipei 11529, Taiwan. Electronic address: [email protected].
² Genomics Research Center, Academia Sinica, Taipei 11529, Taiwan.
³ Department of Pathology, National Taiwan University Hospital, Taipei 10041, Taiwan.
⁴ Department of Internal Medicine, National Taiwan University Hospital, Taipei 10041, Taiwan.
⁵ Institute of Chemistry, Academia Sinica, Taipei 11529, Taiwan.
⁶ Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697, USA.
⁷ Genomics Research Center, Academia Sinica, Taipei 11529, Taiwan; Drug Development Center, China Medical University, Taichung 40402, Taiwan. Electronic address: [email protected].

PMID: 30853214
DOI: 10.1016/j.cmet.2019.02.005

Abstract

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.

Keywords: KRAS mutation; O-GlcNAcylation; PFK; RNR; RRM1; high glucose; nucleotide imbalance.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetylation / drug effects
Acetylglucosamine / metabolism*
Acetyltransferases / metabolism
Adult
Aged
Animals
Carcinoma, Pancreatic Ductal / chemically induced
Carcinoma, Pancreatic Ductal / genetics
Carcinoma, Pancreatic Ductal / metabolism
Carcinoma, Pancreatic Ductal / pathology
Cell Transformation, Neoplastic / chemically induced*
Cell Transformation, Neoplastic / genetics
Cell Transformation, Neoplastic / metabolism
Cells, Cultured
DNA Damage / genetics
Dose-Response Relationship, Drug
Enzymes / genetics
Enzymes / metabolism*
Female
Glucose / adverse effects
Glucose / pharmacology*
HEK293 Cells
Humans
Infant, Newborn
Male
Metabolic Networks and Pathways / drug effects
Metabolic Networks and Pathways / genetics
Mice
Mice, Inbred C57BL
Middle Aged
Mutagenesis / drug effects
Mutation / drug effects
Nucleotides / metabolism*
Pancreas / drug effects*
Pancreas / metabolism
Pancreatic Neoplasms / chemically induced
Pancreatic Neoplasms / genetics
Pancreatic Neoplasms / metabolism
Pancreatic Neoplasms / pathology
Protein Processing, Post-Translational / drug effects
Proto-Oncogene Proteins p21(ras) / genetics*
Proto-Oncogene Proteins p21(ras) / metabolism
Young Adult

Substances

Enzymes
KRAS protein, human
Nucleotides
Acetyltransferases
Proto-Oncogene Proteins p21(ras)
Glucose
Acetylglucosamine