胶质瘤是最常见的颅内恶性肿瘤，临床上还缺乏有效的治疗手段。我们最近的研究发现TRIM24作为转录共激活子与乙酰化的组蛋白H3K23结合，招募并激活STAT3转录活性，导致EGFR驱动的胶质瘤的恶性增殖（Nature Communications, 2017）。但是，TRIM24激活并维持STAT3转录活性的机制并不清楚。本项目拟在前期研究的基础上，利用临床来源的胶质瘤干细胞系、颅内原位成瘤模型、泛素化分析等方法，阐明TRIM24作为E3泛素连接酶，通过调节磷酸酶TC45的泛素化及稳定性来维持STAT3持续磷酸化和高转录活性的分子机制；同时，探讨TRIM24抑制剂联合放化疗延缓胶质瘤进展的可行性。本项目不仅有助于揭示胶质瘤发生发展的新机制，而且为临床靶向治疗和药物设计提供理论依据。

Glioblastoma is the most malignant and lethal tumor in central nervous system. Recently we show that TRIM24 functions as a transcriptional co-activator and recruits STAT3, leading to stabilized STAT3-chromatin interactions and subsequent activation of STAT3 downstream signaling, thereby enhancing EGFR-driven tumorigenesis. However, the mechanism by which TRIM24 activates STAT3 transcriptional activities is still unclear. In this project, we hypothesize that TRIM24 functions as an E3 ligase to mediate the ubiquitination and stability of TC45 (the nuclear form of T cell protein tyrosine phosphatase TC-PTP) , thereby maintaining STAT3 phosphorylation and activation and promoting tumorigenesis. We will also explore the functions of TRIM24 inhibitor in glioma tumorigenesis using orthotopic xenograft brain tumorigenesis. This will help not only to understand the molecular mechanisms of gliomagenesis, but also to provide potential research basis for clinical therapy.