Ablation of EWS-FLI1 by USP9X inhibition suppresses cancer cell growth in Ewing sarcoma

Shan Wang, Xiaofang Huo, Yiping Yang, Yingxi Mo, Rahul K. Kollipara, Ralf Kittler

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article number215984
JournalCancer Letters
Volume552
DOIs
StatePublished - Jan 1 2023

Keywords

  • EWS-FLI1
  • Ewing sarcoma
  • USP9X
  • Ubiquitination
  • WP1130

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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