2. Academic Validation
  3. Methylation of KRAS by SETD7 promotes KRAS degradation in non-small cell lung cancer

Methylation of KRAS by SETD7 promotes KRAS degradation in non-small cell lung cancer

  • Cell Rep. 2023 Sep 6;42(9):113003. doi: 10.1016/j.celrep.2023.113003.
Cheng-Yao Chiang 1,  Songqing Fan 2,  Hongmei Zheng 2,  Wenjun Guo 1,  Zehan Zheng 1,  Yihua Sun 3,  Chuanqi Zhong 4,  Juan Zeng 5,  Shuaihu Li 1,  Min Zhang 1,  Tian Xiao 6,  Duo Zheng 7
Affiliations

Affiliations

  • 1 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.
  • 2 Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
  • 3 Department of Thoracic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
  • 4 State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China.
  • 5 School of Biomedical Engineering, Guangdong Medical University, Dongguan, Guangdong 523808, China.
  • 6 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. Electronic address: txiao@szu.edu.cn.
  • 7 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. Electronic address: dzheng@szu.edu.cn.
PMID: 37682707 DOI: 10.1016/j.celrep.2023.113003
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.

Keywords

CP: Cancer; CP: Molecular biology; KRAS; RABGEF1; SETD7; lysine methylation; non-small cell lung cancer.

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