Methylation of KRAS by SETD7 promotes KRAS degradation in non-small cell lung cancer
Cheng-Yao Chiang,
Songqing Fan,
Hongmei Zheng,
Wenjun Guo,
Zehan Zheng,
Yihua Sun,
Chuanqi Zhong,
Juan Zeng,
Shuaihu Li,
Min Zhang,
Tian Xiao,
Duo Zheng
Affiliations
Cheng-Yao Chiang
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
Songqing Fan
Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
Hongmei Zheng
Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
Wenjun Guo
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
Zehan Zheng
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
Yihua Sun
Department of Thoracic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China
Chuanqi Zhong
State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China
Juan Zeng
School of Biomedical Engineering, Guangdong Medical University, Dongguan, Guangdong 523808, China
Shuaihu Li
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
Min Zhang
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
Tian Xiao
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; Corresponding author
Duo Zheng
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; Corresponding author
Summary: 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.
