2. Academic Validation
  3. Ubiquitin-specific protease 22 controls melanoma metastasis and vulnerability to ferroptosis through targeting SIRT1/PTEN/PI3K signaling

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

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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