尤文氏肉瘤是青少年常见的第二大恶性骨肿瘤，目前其化疗停留在细胞毒类药物，毒副作用大，因此亟需新的靶向治疗药物。EWS基因与FLI1、ERG等转录因子重排形成的EWS-ETS融合蛋白是驱动尤文氏肉瘤发生的基础，但多年来直接靶向EWS融合型癌蛋白的抗癌药物研发并未成功，我们以EWS融合型癌蛋白的泛素化降解为突破口，建立了调控其泛素化动态修饰的泛素修饰酶筛选模型，并发现去泛素化酶JOSD1可调控其去泛素化，提示JOSD1可能是抗尤文氏肉瘤的药物新靶点。在此基础上，本研究将以泛素连接酶和去泛素化酶两个双向调控酶为切入点，紧紧围绕EWS融合型癌蛋白的泛素化动态修饰，从泛素化修饰的来路和去路两个模块开展针对EWS融合型癌蛋白的抗肿瘤药物靶点的系统性研究工作。本项目的实施不仅为抗肿瘤药物的研发提供崭新的靶点，还可阐明调控EWS融合型癌蛋白泛素化修饰的动态酶学过程，揭示其与肿瘤发生发展的相关性。

Ewing's sarcoma is the second most common bone cancer in children and adolescents, which has a high degree of malignancy. The chemotherapy of Ewing's sarcoma remains in the cytotoxic drugs, which have great toxic and side effects. It is urgent to find new targeted drugs. The fusion protein of EWS-ETS rearranged by EWS and transcription factors, such as FLI1 or ERG, drives tumorigenesis of Ewing's sarcoma. Over the years, it fails to develop anticancer drugs by direct targeting of EWS-ETS fusion onco-proteins. It is necessary to explore new strategies to overcome the defect. We are now focusing on the ubiquitination of EWS-ETS fusion onco-proteins, and have established a model to screen enzymes that regulate its ubiquitination process. The deubiquitinating enzyme JOSD1 has beed found to impact the deubiquitination of EWS-ETS fusion onco-proteins, suggesting that JOSD1 may be a drug target for treatment of Ewing's sarcoma. Based on the above findings, this project will focus on the ubiquitin ligase and deubiquitinase which can direct regulate the dynamic ubiquitination of EWS-ETS fusion onco-proteins, verify their role in regulating the ubiquitination and stability of EWS-ETS fusion onco-proteins. Our study will not only provide new targets for the development of anticancer drugs, but also clarify the dynamic process of enzymes that regulate EWS-ETS fusion onco-proteins, reveal its association with tumorigenesis.