Ubiquitin-specific protease 22 controls melanoma metastasis and vulnerability to ferroptosis through targeting SIRT1/PTEN/PI3K signaling

  • MedComm (2020). 2024 Aug 12;5(8):e684. doi: 10.1002/mco2.684.
Huiyan Sun  1  2  3  4  5  6 ,  Yu Meng  1  2  3  4  5 ,  Lei Yao  7 ,  Songtao Du  8 ,  Yayun Li  9 ,  Qian Zhou  1  2  3  4  5 ,  Yihuang Liu  1  2  3  4  5 ,  Yating Dian  1  2  3  4  5 ,  Yuming Sun  10 ,  Xiaomin Wang  11 ,  Xiao-Wei Liang  1  2  3  4  5 ,  Guangtong Deng  1  2  3  4  5 ,  Xiang Chen  1  2  3  4  5 ,  Furong Zeng  12
Affiliations
  • 1. Department of Dermatology Xiangya Hospital Central South University Changsha China.
  • 2. National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology Changsha China.
  • 3. Furong Laboratory Changsha China.
  • 4. Hunan Key Laboratory of Skin Cancer and Psoriasis, Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital Central South University Changsha China.
  • 5. National Clinical Research Center for Geriatric Disorders (Xiangya Hospital) Changsha China.
  • 6. Department of Breast Reconstruction Tianjin Medical University Cancer Institute and Hospital Tianjin China.
  • 7. Department of Liver Surgery Xiangya Hospital Central South University Changsha China.
  • 8. Department of Colorectal Surgical Oncology The Tumor Hospital of Harbin Medical University Harbin China.
  • 9. Department of Dermatology The Third Xiangya Hospital Central South University Changsha China.
  • 10. Department of Plastic and Cosmetic Surgery Xiangya Hospital Central South University Changsha China.
  • 11. Department of Breast Surgery Xiangya Hospital Central South University Changsha China.
  • 12. Department of Oncology Xiangya Hospital Central South University Changsha China.
PMID: 39135915 DOI: 10.1002/mco2.684
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.

Keywords
USP22; ferroptosis; melanoma; metastasis; topotecan.
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