致癌的KRAS突变是非小细胞肺癌（NSCLC）发生和进展的主要驱动因素。然而，KRAS的翻译后修饰（PTM），特别是甲基化，如何修改KRAS的活性，目前仍不清楚。在这里，我们展示了带有SET结构域的组蛋白赖氨酸甲基转移酶7（SETD7）与KRAS相互作用，并在位于182和184位的赖氨酸上对KRAS进行甲基化。SETD7介导的KRAS甲基化导致KRAS的降解和RAS/MEK/ERK信号级联的减弱，使SETD7在NSCLC的体外和体内具有强大的抗肿瘤作用。机制上，KRAS的泛素E3连接酶RABGEF1以依赖于K182/K184甲基化的方式被招募并促进KRAS的降解。值得注意的是，临床NSCLC组织中SETD7与KRAS的蛋白水平呈负相关。在肺腺癌患者中，SETD7和RABGEF1的低表达与预后不良相关。总之，我们的结果定义了SETD7通过调节KRAS的甲基化和降解而发挥抑制肿瘤功能的作用。版权所有© 2023作者。由Elsevier Inc.发表，保留所有权利。

Oncogenic KRAS mutations are a key driver for initiation and progression in non-small cell lung cancer (NSCLC). However, how post-translational modifications (PTMs) of KRAS, especially methylation, modify KRAS activity remain largely unclear. Here, we show that SET domain containing histone lysine methyltransferase 7 (SETD7) interacts with KRAS and methylates KRAS at lysines 182 and 184. SETD7-mediated methylation of KRAS leads to degradation of KRAS and attenuation of the RAS/MEK/ERK signaling cascade, endowing SETD7 with a potent tumor-suppressive role in NSCLC, both in vitro and in vivo. Mechanistically, RABGEF1, a ubiquitin E3 ligase of KRAS, is recruited and promotes KRAS degradation in a K182/K184 methylation-dependent manner. Notably, SETD7 is inversely correlated with KRAS at the protein level in clinical NSCLC tissues. Low SETD7 or RABGEF1 expression is associated with poor prognosis in lung adenocarcinoma patients. Altogether, our results define a tumor-suppressive function of SETD7 that operates via modulating KRAS methylation and degradation.Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.