USP9X 抑制作用消除 EWS-FLI1 可抑制尤文肉瘤中癌细胞的生长。
Ablation of EWS-FLI1 by USP9X inhibition suppresses cancer cell growth in Ewing sarcoma.
机构信息
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.
Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX, USA.
出版信息
Cancer Lett. 2023 Jan 1;552:215984. doi: 10.1016/j.canlet.2022.215984. Epub 2022 Oct 29.
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.
新形成的转录因子 EWS-FLI1 是尤文肉瘤的关键驱动因子。EWS-FLI1 的消融可能为这种恶性肿瘤提供一种有前途的治疗策略。在这里，我们发现去泛素化酶，泛素特异性肽酶 9X 连锁（USP9X）稳定尤文肉瘤中的 EWS-FLI1 蛋白表达。我们表明 USP9X 在尤文肉瘤细胞中结合 EWS-FLI1 的 ETS 结构域，并使 EWS-FLI1 去泛素化，并且 USP9X 和 EWS-FLI1 蛋白表达在临床尤文肉瘤标本中相关。我们发现，用 USP9X 抑制剂 WP1130 处理尤文肉瘤细胞在体外和体内介导 EWS-FLI1 的快速降解，这与尤文肉瘤细胞和肿瘤的生长减少一致。我们的结果表明，USP9X 可能是一种潜在的治疗靶点，可介导尤文肉瘤中 EWS-FLI1 的耗竭。
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