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

• Published in: Cell metabolism 2019-06, Vol.29 (6), p.1334-1349.e10
• Main Authors: Hu, Chun-Mei, Tien, Sui-Chih, Hsieh, Ping-Kun, Jeng, Yung-Ming, Chang, Ming-Chu, Chang, Yu-Ting, Chen, Yi-Ju, Chen, Yu-Ju, Lee, Eva Y.-H.P., Lee, Wen-Hwa
• Format: Article
• Language: English
• Subjects: high glucose; KRAS mutation; nucleotide imbalance; O-GlcNAcylation; PFK; RNR; RRM1
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2019.02.005

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. [Display omitted] •Pancreatic cells exhibit lower phosphofructokinase activity than other cell types•High glucose elevates O-GlcNAcylation and genomic alterations in pancreatic cells•Reduction of RNR activity leads to nucleotide pool imbalance and KRAS mutations•PFK activity alters the sensitivity to high-glucose-induced genomic effects Most pancreatic ductal adenocarcinomas contain activated KRAS mutations required for cancer initiation and maintenance. Here, Hu et al. show that high glucose promotes O-GlcNAcylation on ribonucleotide reductase, leading to nucleotide pool imbalance and KRAS mutations preferentially in pancreatic cells.