2. Academic Validation
  3. USP1 inhibition suppresses the progression of osteosarcoma via destabilizing TAZ

USP1 inhibition suppresses the progression of osteosarcoma via destabilizing TAZ

  • Int J Biol Sci. 2022 May 1;18(8):3122-3136. doi: 10.7150/ijbs.65428.
Putao Yuan 1 2 3,  Zhenhua Feng 1 2,  Hai Huang 1 2 4,  Gangliang Wang 1 2,  Zhijun Chen 1 2 3,  Guang Xu 1 2,  Ziang Xie 1 2,  Zhiwei Jie 1 2,  Xiangde Zhao 1 2,  Qingliang Ma 1 2,  Shiyu Wang 1 2,  Yang Shen 1 2,  Yizhen Huang 1 2,  Ying Han 1 2,  Huali Ye 1 2,  Jiying Wang 1 2,  Peihua Shi 1 2 3,  Xuewu Sun 1 2 3
Affiliations

Affiliations

  • 1 Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine.
  • 2 Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province.
  • 3 Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, China.
  • 4 903RD Hospital of Pla, Hangzhou, China.
PMID: 35637948 DOI: 10.7150/ijbs.65428
Abstract

Mutations and altered expression of deubiquitinating Enzymes (DUBs) profoundly influence tumor progression. Ubiquitin-Specific Protease 1 (USP1) is a well-characterized human DUB reportedly overexpressed in and associated with maintaining the mesenchymal stem cell status of osteosarcoma (OS); however, the potential mechanisms of USP1 in OS remain poorly understood. In this study, we identified that USP1 directly interacts with Transcriptional Co-Activator With PDZ-Binding Motif (TAZ) in OS cell lines, and with mechanistic analysis indicating that the anti-OS effects of USP1 inhibition could be partially attributed to TAZ instability, with its reduced nuclear accumulation responsible for a subsequent decrease in the expression of downstream genes associated with the Hippo signaling pathway. Moreover, pharmacological inhibition USP1 by ML323 presented the similar effects on Hippo signaling pathway and suppressed OS growth and metastasis both in vitro and in vivo. Taken together, our results revealed a novel molecular mechanism underlying the function of USP1 in OS and a potential role of ML323 as a therapeutic strategy for the clinical treatment of OS.

Keywords

Hippo; ML323; Osteosarcoma; TAZ; USP1; Ubiquitin.

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