Pharmacological targeting of casein kinase 1δ suppresses oncogenic NRAS-driven melanoma
Abstract Activating mutations in NRAS account for 15–20% of melanoma, yet effective anti-NRAS therapies are still lacking. In this study, we unveil the casein kinase 1δ (CK1δ) as an uncharacterized regulator of oncogenic NRAS mutations, specifically Q61R and Q61K, which are the most prevalent NRAS m...
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| Format: | Article |
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Nature Portfolio
2024-11-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-54140-1 |
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| author | Yalei Wen Hui Wang Xiao Yang Yingjie Zhu Mei Li Xiuqing Ma Lei Huang Rui Wan Caishi Zhang Shengrong Li Hongling Jia Qin Guo Xiaoyun Lu Zhengqiu Li Xiangchun Shen Qiushi Zhang Lu Si Chengqian Yin Tongzheng Liu |
| author_facet | Yalei Wen Hui Wang Xiao Yang Yingjie Zhu Mei Li Xiuqing Ma Lei Huang Rui Wan Caishi Zhang Shengrong Li Hongling Jia Qin Guo Xiaoyun Lu Zhengqiu Li Xiangchun Shen Qiushi Zhang Lu Si Chengqian Yin Tongzheng Liu |
| author_sort | Yalei Wen |
| collection | DOAJ |
| description | Abstract Activating mutations in NRAS account for 15–20% of melanoma, yet effective anti-NRAS therapies are still lacking. In this study, we unveil the casein kinase 1δ (CK1δ) as an uncharacterized regulator of oncogenic NRAS mutations, specifically Q61R and Q61K, which are the most prevalent NRAS mutations in melanoma. The genetic ablation or pharmacological inhibition of CK1δ markedly destabilizes NRAS mutants and suppresses their oncogenic functions. Moreover, we identify USP46 as a bona fide deubiquitinase of NRAS mutants. Mechanistically, CK1δ directly phosphorylates USP46 and activates its deubiquitinase activity towards NRAS mutants, thus promoting oncogenic NRAS-driven melanocyte malignant transformation and melanoma progression in vitro and in vivo. Our findings underscore the significance of the CK1δ-USP46 axis in stabilizing oncogenic NRAS mutants and provide preclinical evidence that targeting this axis holds promise as a therapeutic strategy for human melanoma harboring NRAS mutations. |
| format | Article |
| id | doaj-art-83e26542cf344856a8abf2d239e81390 |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-83e26542cf344856a8abf2d239e813902025-08-20T02:33:06ZengNature PortfolioNature Communications2041-17232024-11-0115111910.1038/s41467-024-54140-1Pharmacological targeting of casein kinase 1δ suppresses oncogenic NRAS-driven melanomaYalei Wen0Hui Wang1Xiao Yang2Yingjie Zhu3Mei Li4Xiuqing Ma5Lei Huang6Rui Wan7Caishi Zhang8Shengrong Li9Hongling Jia10Qin Guo11Xiaoyun Lu12Zhengqiu Li13Xiangchun Shen14Qiushi Zhang15Lu Si16Chengqian Yin17Tongzheng Liu18Research Institute for Maternal and Child Health, The Affiliated Guangdong Second Provincial General Hospital, Postdoctoral Research Station of Traditional Chinese Medicine, School of Pharmacy, Jinan UniversityInstitute of Cancer Research, Shenzhen Bay LaboratoryCollege of Pharmacy/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China, Jinan UniversityCollege of Pharmacy/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China, Jinan UniversityCollege of Pharmacy/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China, Jinan UniversityCollege of Pharmacy/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China, Jinan UniversityCollege of Pharmacy/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China, Jinan UniversityCollege of Pharmacy/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China, Jinan UniversityCollege of Pharmacy/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China, Jinan UniversityCollege of Pharmacy/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China, Jinan UniversityDepartment of Medical Biochemistry and Molecular Biology, School of Medicine, Jinan UniversityDepartment of Pathology, Shanxi Provincial People’s HospitalCollege of Pharmacy/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China, Jinan UniversityCollege of Pharmacy/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China, Jinan UniversityThe State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical UniversityResearch Institute for Maternal and Child Health, The Affiliated Guangdong Second Provincial General Hospital, Postdoctoral Research Station of Traditional Chinese Medicine, School of Pharmacy, Jinan UniversityKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Melanoma and Sarcoma, Peking University Cancer Hospital and Research InstituteInstitute of Cancer Research, Shenzhen Bay LaboratoryResearch Institute for Maternal and Child Health, The Affiliated Guangdong Second Provincial General Hospital, Postdoctoral Research Station of Traditional Chinese Medicine, School of Pharmacy, Jinan UniversityAbstract Activating mutations in NRAS account for 15–20% of melanoma, yet effective anti-NRAS therapies are still lacking. In this study, we unveil the casein kinase 1δ (CK1δ) as an uncharacterized regulator of oncogenic NRAS mutations, specifically Q61R and Q61K, which are the most prevalent NRAS mutations in melanoma. The genetic ablation or pharmacological inhibition of CK1δ markedly destabilizes NRAS mutants and suppresses their oncogenic functions. Moreover, we identify USP46 as a bona fide deubiquitinase of NRAS mutants. Mechanistically, CK1δ directly phosphorylates USP46 and activates its deubiquitinase activity towards NRAS mutants, thus promoting oncogenic NRAS-driven melanocyte malignant transformation and melanoma progression in vitro and in vivo. Our findings underscore the significance of the CK1δ-USP46 axis in stabilizing oncogenic NRAS mutants and provide preclinical evidence that targeting this axis holds promise as a therapeutic strategy for human melanoma harboring NRAS mutations.https://doi.org/10.1038/s41467-024-54140-1 |
| spellingShingle | Yalei Wen Hui Wang Xiao Yang Yingjie Zhu Mei Li Xiuqing Ma Lei Huang Rui Wan Caishi Zhang Shengrong Li Hongling Jia Qin Guo Xiaoyun Lu Zhengqiu Li Xiangchun Shen Qiushi Zhang Lu Si Chengqian Yin Tongzheng Liu Pharmacological targeting of casein kinase 1δ suppresses oncogenic NRAS-driven melanoma Nature Communications |
| title | Pharmacological targeting of casein kinase 1δ suppresses oncogenic NRAS-driven melanoma |
| title_full | Pharmacological targeting of casein kinase 1δ suppresses oncogenic NRAS-driven melanoma |
| title_fullStr | Pharmacological targeting of casein kinase 1δ suppresses oncogenic NRAS-driven melanoma |
| title_full_unstemmed | Pharmacological targeting of casein kinase 1δ suppresses oncogenic NRAS-driven melanoma |
| title_short | Pharmacological targeting of casein kinase 1δ suppresses oncogenic NRAS-driven melanoma |
| title_sort | pharmacological targeting of casein kinase 1δ suppresses oncogenic nras driven melanoma |
| url | https://doi.org/10.1038/s41467-024-54140-1 |
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