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

Cell Reports (Sep 2023)

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

Journal volume & issue: Vol. 42, no. 9
p. 113003

Abstract

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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.

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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