Abstract：
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.
摘要：
致癌KRAS突变是非小细胞肺癌（NSCLC）发生和进展的关键驱动因素。然而,KRAS的翻译后修饰（PTM），尤其是甲基化，修改KRAS活性仍不清楚。这里,我们显示，SET结构域含有组蛋白赖氨酸甲基转移酶7（SETD7）与KRAS相互作用，并在赖氨酸182和184处甲基化KRAS。SETD7介导的KRAS甲基化导致KRAS的降解和RAS/MEK/ERK信号级联的衰减,赋予SETD7在非小细胞肺癌中有效的肿瘤抑制作用，在体外和体内。机械上,RABGEF1，一种KRAS的泛素E3连接酶，被募集并以K182/K184甲基化依赖性方式促进KRAS降解。值得注意的是,在临床NSCLC组织中,SETD7在蛋白水平上与KRAS呈负相关。低SETD7或RABGEF1表达与肺腺癌患者的不良预后相关。总之,我们的结果定义了SETD7的肿瘤抑制功能,其通过调节KRAS甲基化和降解起作用.
