Ablation of EWS-FLI1 by USP9X inhibition suppresses cancer cell growth in Ewing sarcoma.
The neomorphic transcription factor EWS-FLI1 is a key driver of Ewing sarcoma. Ablation of EWS-FLI1 may present a promising therapeutic strategy for this malignancy. Here we found that the deubiquitinase, ubiquitin specific peptidase 9 X-linked (USP9X) stabilizes EWS-FLI1 protein expression in Ewing sarcoma. We show that USP9X binds the ETS ... domain of EWS-FLI1 in Ewing sarcoma cells and deubiquitinates EWS-FLI1 and that USP9X and EWS-FLI1 protein expression is correlated in clinical Ewing sarcoma specimens. We found that treatment of Ewing sarcoma cells with the USP9X inhibitor WP1130 mediates rapid EWS-FLI1 degradation in vitro and in vivo which coincides with reduced growth of Ewing sarcoma cells and tumors. Our results suggest that USP9X might be a potential therapeutic target to mediate EWS-FLI1 depletion in Ewing sarcoma.
Mesh Terms:
Cell Line, Tumor, Cell Transformation, Neoplastic, Gene Expression Regulation, Neoplastic, Humans, Oncogene Proteins, Fusion, Proto-Oncogene Protein c-fli-1, RNA-Binding Protein EWS, Sarcoma, Ewing, Ubiquitin Thiolesterase
Cell Line, Tumor, Cell Transformation, Neoplastic, Gene Expression Regulation, Neoplastic, Humans, Oncogene Proteins, Fusion, Proto-Oncogene Protein c-fli-1, RNA-Binding Protein EWS, Sarcoma, Ewing, Ubiquitin Thiolesterase
Cancer Lett
Date: Jan. 01, 2023
PubMed ID: 36330954
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