Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, International Cancer Center, Department of Cell Biology and Genetics, Shenzhen University Medical School, Thoracic Surgery Department of the First Affiliated Hospital, Shenzhen University, Shenzhen 518055, China.
Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
Cell Rep. 2023 Sep 26;42(9):113003. doi: 10.1016/j.celrep.2023.113003. Epub 2023 Sep 8.
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.
致癌性 KRAS 突变是引发非小细胞肺癌（NSCLC）发生和进展的关键驱动因素。然而，KRAS 的翻译后修饰（PTMs），尤其是甲基化，如何修饰 KRAS 的活性在很大程度上仍不清楚。在这里，我们表明 SET 结构域包含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 降解和 RAS/MEK/ERK 信号级联的衰减，使 SETD7 在 NSCLC 中具有强大的肿瘤抑制作用，无论是在体外还是体内。在机制上，RABGEF1 是 KRAS 的一种泛素 E3 连接酶，以 K182/K184 甲基化依赖性的方式被募集并促进 KRAS 降解。值得注意的是，在临床 NSCLC 组织中，SETD7 与 KRAS 在蛋白质水平上呈负相关。低 SETD7 或 RABGEF1 表达与肺腺癌患者的预后不良相关。总之，我们的研究结果定义了 SETD7 的肿瘤抑制功能，其通过调节 KRAS 甲基化和降解来发挥作用。
