近日，基因体研究中心李文华研究组的最新研究揭示了高糖通过影响一些关键酶的O-乙酰氨基葡萄糖化（O-GlcNAcylation）修饰触发核苷酸失衡，并诱发胰腺细胞中的KRAS基因突变。相关论文发表在2019年6月出版的《Cell Metabolism》杂志上。

该研究组发现，在高糖培养条件下，胰腺细胞中的O-GlcNAcylation修饰水平显著升高，使得磷酸果糖激酶（PFK）活性低于其他类型的细胞。这种翻译后修饰专一地降低了核苷酸还原酶（RNR）的活性，并由此导致dNTP含量的缺乏、基因组DNA中KRAS突变、以及细胞转变。这些研究结果为糖代谢紊乱与基因组不稳定建立了一种机制上的关联并解释了为什么KRAS的原癌突变会偏好在胰腺细胞中发生。

据了解，KRAS突变是在大约90%的胰腺导管腺癌(PDACs)发生的早期事件。然而，对于KRAS突变为何偏好在胰腺癌中突变以及哪些因素促使了这些突变，人们的认知还甚少。此外，尽管异常的碳水化合物代谢与胰腺癌的高风险有关，但KRAS突变与糖代谢之间是否存在直接关系仍是未知数。

附：英文原文

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

Author: 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

Issue&Volume: Jun 04, 2019 Volume 29Issue 6

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.

DOI: https://doi.org/10.1016/j.cmet.2019.02.005

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(19)30069-5