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...

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Bibliographic Details
Published inCancer letters Vol. 552; p. 215984
Main Authors Wang, Shan, Huo, Xiaofang, Yang, Yiping, Mo, Yingxi, Kollipara, Rahul K., Kittler, Ralf
Format Journal Article
LanguageEnglish
Published Ireland Elsevier B.V 01.01.2023
Elsevier Limited
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Summary: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. •USP9X interacts with EWS-FLI1 through the ETS domain.•USP9X deubiquitinates and stabilizes EWS-FLI1.•USP9X inhibition by WP1130 could reduce cell proliferation of Ewing sarcoma.•USP9X loss and inhibition affects migration of Ewing sarcoma cells.
ISSN:0304-3835
1872-7980
DOI:10.1016/j.canlet.2022.215984