TRIM24调控糖皮质激素受体GR转录活性在T细胞淋巴瘤发生发展中的作用及机制研究

转录调控因子是细胞转录调控网络中的关键组分，其功能异常会导致肿瘤的发生发展。肿瘤细胞对功能失调的转录调控因子常具有高度依赖性，所以鉴定这些转录调控因子并阐明其调控基因表达的分子机制显得尤为重要。我们前期研究发现转录共调节因子TRIM24的活性在T细胞淋巴瘤（TCL）组织中显著上调，进一步研究表明TRIM24能够抑制糖皮质激素受体GR的转录活性，促进TCL细胞的恶性增殖，并增强TCL细胞的致瘤性和对糖皮质激素的耐药性，但具体的转录调控分子机制有待进一步研究。因此本项目拟开展：利用Trim24敲除小鼠建立TCL模型来研究TRIM24在TCL中的作用，并进行临床相关性验证；并以TRIM24介导蛋白泛素化降解和特异性识别组蛋白翻译后修饰这两方面功能来深入解析TRIM24调控GR转录复合体功能的分子机制，从而明确TRIM24促进TCL发生发展的作用机理，并为TCL的靶向药物研发提供新思路。

Transcriptional regulatory factors (TRF) are the hubs in the transcription regulatory network, and TRF dysfunction would cause dysregulated transcriptional programs, eventually resulting in tumorigenesis. These dysregulated programs can cause cancer cells to become highly dependent on certain TRF. Therefore, it is critical to identify the dysfunctional TRF in cancer and define the underlying mechanisms. Our preliminary data has shown that the activity of TRIM24 in T cell lymphoma (TCL) increased hugely, and further study has demonstrated that TRIM24 could inhibit the transcriptional activity of glucocorticoid receptor (GR), promote the proliferation and tumorigenicity of TCL cells and enhance the resistance to glucocorticoid treatment, but the underlying mechanisms need to be elucidated. Therefore, we plan to investigate the role of TRIM24 in TCL mouse models using our Trim24 knockout strain, and further determine the correlation of the underlying mechanisms and the clinical phenotype using TCL patients’ specimen. Furthermore, we plan to investigate the mechanisms by which TRIM24 regulates GR transcriptional complex based on the functions of TRIM24 as a E3 ubiquitin ligase and Histone post-translational modification (PTM) reader, and analyze the affected gene expression profile downstream GR and their effects on TCL development. Successful completion of these studies will further understand the mechanisms underlying the TCL development and provide a novel drug target for treating TCL.