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Pharmacological targeting of casein kinase 1δ suppresses oncogenic NRAS-driven melanoma

Author

Listed:
  • Yalei Wen

    (Jinan University
    Guizhou Medical University
    Jinan University)

  • Hui Wang

    (Shenzhen Bay Laboratory
    Shenzhen Medical Academy of Research and Translation (SMART))

  • Xiao Yang

    (Jinan University)

  • Yingjie Zhu

    (Jinan University)

  • Mei Li

    (Jinan University)

  • Xiuqing Ma

    (Jinan University)

  • Lei Huang

    (Jinan University)

  • Rui Wan

    (Jinan University)

  • Caishi Zhang

    (Jinan University)

  • Shengrong Li

    (Jinan University)

  • Hongling Jia

    (Jinan University)

  • Qin Guo

    (Shanxi Provincial People’s Hospital)

  • Xiaoyun Lu

    (Jinan University)

  • Zhengqiu Li

    (Jinan University)

  • Xiangchun Shen

    (Guizhou Medical University)

  • Qiushi Zhang

    (Jinan University)

  • Lu Si

    (Peking University Cancer Hospital and Research Institute)

  • Chengqian Yin

    (Shenzhen Bay Laboratory
    Shenzhen Medical Academy of Research and Translation (SMART))

  • Tongzheng Liu

    (Jinan University
    Guizhou Medical University
    Jinan University)

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.

Suggested Citation

  • 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 Z, 2024. "Pharmacological targeting of casein kinase 1δ suppresses oncogenic NRAS-driven melanoma," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-54140-1
    DOI: 10.1038/s41467-024-54140-1
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    References listed on IDEAS

    as
    1. Tongzheng Liu & Jia Yu & Min Deng & Yujiao Yin & Haoxing Zhang & Kuntian Luo & Bo Qin & Yunhui Li & Chenming Wu & Tao Ren & Yang Han & Peng Yin & JungJin Kim & SeungBaek Lee & Jing Lin & Lizhi Zhang &, 2017. "CDK4/6-dependent activation of DUB3 regulates cancer metastasis through SNAIL1," Nature Communications, Nature, vol. 8(1), pages 1-12, April.
    2. Li-Yu Huang & Junjie Zhao & Hao Chen & Lixin Wan & Hiroyuki Inuzuka & Jianping Guo & Xuhong Fu & Yangyang Zhai & Zhaoning Lu & Xuefei Wang & Ze-Guang Han & Yihong Sun & Wenyi Wei, 2018. "SCFFBW7-mediated degradation of Brg1 suppresses gastric cancer metastasis," Nature Communications, Nature, vol. 9(1), pages 1-12, December.
    3. Brandon M. Murphy & Elizabeth M. Terrell & Venkat R. Chirasani & Tirzah J. Weiss & Rachel E. Lew & Andrea M. Holderbaum & Aastha Dhakal & Valentina Posada & Marie Fort & Michael S. Bodnar & Leiah M. C, 2022. "Enhanced BRAF engagement by NRAS mutants capable of promoting melanoma initiation," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
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