Ablation of EWS-FLI1 by USP9X inhibition suppresses cancer cell growth in Ewing sarcoma
- Cancer Lett. 2023 Jan 1:552:215984. doi: 10.1016/j.canlet.2022.215984.
- 1. Department of Research, Guangxi Medical University Cancer Hospital, Nanning, Guangxi Zhuang Autonomous Region, China; Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX, USA.
- 2. Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX, USA.
- 3. Department of Research, Guangxi Medical University Cancer Hospital, Nanning, Guangxi Zhuang Autonomous Region, China.
- 4. Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX, USA; Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA; Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA; Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA. Electronic address: [email protected].
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.