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

被引：9

作者：

Wang, Shan ^{[1
,2
]}

Huo, Xiaofang ^{[2
]}

Yang, Yiping ^{[1
]}

Mo, Yingxi ^{[1
]}

Kollipara, Rahul K. ^{[2
]}

Kittler, Ralf ^{[2
,3
,4
,5
,6
]}

机构：

[1] Guangxi Med Univ, Dept Res, Canc Hosp, Nanning, Guangxi Zhuang, Peoples R China

[2] Univ Texas Southwestern Med Ctr, Eugene McDermott Ctr Human Growth & Dev, Dallas, TX USA

[3] Univ Texas Southwestern Med Ctr Dallas, Simmons Comprehens Canc Ctr, Dallas, TX USA

[4] Univ Texas Southwestern Med Ctr Dallas, Dept Pharmacol, Dallas, TX USA

[5] Univ Texas Southwestern Med Ctr Dallas, Green Ctr Reprod Biol Sci, Dallas, TX USA

[6] UT Southwestern Med Ctr, McDermott Ctr Human Growth & Dev, 5323 Harry Hines Blvd, Dallas, TX 75390 USA

来源：

CANCER LETTERS | 2023年 / 552卷

关键词：

Ewing sarcoma; USP9X; EWS-FLI1; Ubiquitination; WP1130; SHORT INTERFERING RNAS; EWS/FLI-1; PHENOTYPE; SURVIVAL; THERAPY; PROGRAM; FUSION;

D O I：

10.1016/j.canlet.2022.215984

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页数：8

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