Pharmacological targeting of casein kinase 1δ suppresses oncogenic NRAS-driven melanoma
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.
Authors
- Caishi Zhang (ORCID: https://orcid.org/0000-0002-9225-6198)
- Chengqian Yin (ORCID: https://orcid.org/0000-0003-4247-6245)
- Lu Si (ORCID: https://orcid.org/0000-0002-2123-9761)
- Xiaoyun Lu (ORCID: https://orcid.org/0000-0001-7931-6873)
- Xiao Yang (ORCID: https://orcid.org/0000-0002-9573-8782)
- Zhengqiu Li (ORCID: https://orcid.org/0000-0002-0433-2147)
- Xiangchun Shen (ORCID: https://orcid.org/0000-0002-4333-9106)
- Yalei Wen
- Tongzheng Liu
- Xiuqing Ma (ORCID: https://orcid.org/0000-0003-2585-9412)
- Mei Li (ORCID: https://orcid.org/0000-0002-8811-5077)
- Yingjie Zhu (ORCID: https://orcid.org/0009-0006-1438-4641)
- Rui Wan (ORCID: https://orcid.org/0000-0002-7177-7736)
- Qiushi Zhang (ORCID: https://orcid.org/0000-0001-5169-2092)
- Lei Huang (ORCID: https://orcid.org/0000-0002-0568-0645)
- Hong-Ling Jia (ORCID: https://orcid.org/0000-0003-4707-0949)
- Qin Guo (ORCID: https://orcid.org/0000-0001-5319-3510)
- Shengrong Li (ORCID: https://orcid.org/0009-0009-7064-9976)
- Hui Wang (ORCID: https://orcid.org/0000-0002-3558-0055)
Institutions
- Guiyang Medical University (CN)
- Jinan University (CN)
- Shanxi Medical University (CN)
- Peking University (CN)
- Shenzhen Metro (China) (CN)
- Peking University Cancer Hospital (CN)
- Shenzhen Bay Laboratory (CN)
- Guangdong Provincial Hospital of Traditional Chinese Medicine (CN)
- Ministry of Education (TH)
- Ministry of Education (ET)
- Shenzhen Academy of Aerospace Technology (CN)
- Shanxi Provincial People’s Hospital (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-11-21
- DOI
- https://doi.org/10.1038/s41467-024-54140-1
- Citations
- 7
- Primary Topic
- Protein Degradation and Inhibitors
- Type
- article
- Field-Weighted Citation Impact
- 1.64
Funders
- National Natural Science Foundation of China
- China Postdoctoral Science Foundation
- Jinan University
- Beijing Municipal Administration of Hospitals
- Shenzhen Bay Laboratory
- Fundamental Research Funds for the Central Universities
- Basic and Applied Basic Research Foundation of Guangdong Province