Methylation of KRAS by SETD7 promotes KRAS degradation in non-small cell lung cancer
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...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-09-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124723010148 |
| _version_ | 1827822375702364160 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Cheng-Yao Chiang |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-12T01:56:05Z |
| format | Article |
| id | doaj.art-59d0d81c26bc4304bd1ffb60ae523376 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-03-12T01:56:05Z |
| publishDate | 2023-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-59d0d81c26bc4304bd1ffb60ae5233762023-09-08T04:33:12ZengElsevierCell Reports2211-12472023-09-01429113003Methylation of KRAS by SETD7 promotes KRAS degradation in non-small cell lung cancerCheng-Yao Chiang0Songqing Fan1Hongmei Zheng2Wenjun Guo3Zehan Zheng4Yihua Sun5Chuanqi Zhong6Juan Zeng7Shuaihu Li8Min Zhang9Tian Xiao10Duo Zheng11Guangdong 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, ChinaDepartment of Pathology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410008, ChinaDepartment of Pathology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410008, ChinaGuangdong 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, ChinaGuangdong 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, ChinaDepartment of Thoracic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, ChinaState Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, ChinaSchool of Biomedical Engineering, Guangdong Medical University, Dongguan, Guangdong 523808, ChinaGuangdong 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, ChinaGuangdong 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, ChinaGuangdong 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 authorGuangdong 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 authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2211124723010148CP: Molecular biologyCP: Cancer |
| spellingShingle | 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 Methylation of KRAS by SETD7 promotes KRAS degradation in non-small cell lung cancer Cell Reports CP: Molecular biology CP: Cancer |
| title | Methylation of KRAS by SETD7 promotes KRAS degradation in non-small cell lung cancer |
| title_full | Methylation of KRAS by SETD7 promotes KRAS degradation in non-small cell lung cancer |
| title_fullStr | Methylation of KRAS by SETD7 promotes KRAS degradation in non-small cell lung cancer |
| title_full_unstemmed | Methylation of KRAS by SETD7 promotes KRAS degradation in non-small cell lung cancer |
| title_short | Methylation of KRAS by SETD7 promotes KRAS degradation in non-small cell lung cancer |
| title_sort | methylation of kras by setd7 promotes kras degradation in non small cell lung cancer |
| topic | CP: Molecular biology CP: Cancer |
| url | http://www.sciencedirect.com/science/article/pii/S2211124723010148 |
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