1. Ubiquitin-specific protease 22 controls melanoma metastasis and vulnerability to ferroptosis through targeting SIRT1/PTEN/PI3K signaling.
- Author
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Sun H, Meng Y, Yao L, Du S, Li Y, Zhou Q, Liu Y, Dian Y, Sun Y, Wang X, Liang XW, Deng G, Chen X, and Zeng F
- Abstract
Metastasis is a major contributing factor that affects the prognosis of melanoma patients. Nevertheless, the underlying molecular mechanisms involved in melanoma metastasis are not yet entirely understood. Here, we identified ubiquitin-specific protease 22 (USP22) as a pro-oncogenic protein in melanoma through screening the survival profiles of 52 ubiquitin-specific proteases (USPs). USP22 demonstrates a strong association with poor clinical outcomes and is significantly overexpressed in melanoma. Ablation of USP22 expression remarkably attenuates melanoma migration, invasion, and epithelial-mesenchymal transition in vitro and suppresses melanoma metastasis in vivo. Mechanistically, USP22 controls melanoma metastasis through the SIRT1/PTEN/PI3K pathway. In addition, we conducted an United States Food and Drug Administration-approved drug library screening and identified topotecan as a clinically applicable USP22-targeting molecule by promoting proteasomal degradation of USP22. Finally, we found that both pharmacological and genetic silence of USP22 sensitize RSL3-induced ferroptosis through suppressing the PI3K/Akt/mTOR pathway and its downstream SCD, and ferroptosis inhibitor could partly rescued the decreased lung metastasis by topotecan in vivo. Overall, our findings reveal a prometastatic role of USP22 and identify topotecan as a potent USP22-targeting drug to limit melanoma metastasis., Competing Interests: The authors have no relevant financial or nonfinancial interests to disclose., (© 2024 The Author(s). MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd.)
- Published
- 2024
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