OTUB1调控pSTAT3去泛素化影响NSCLC发生发展的机制研究

非小细胞肺癌（NSCLC）是发病率和死亡率极高的恶性肿瘤。研究发现转录因子STAT3活化能促进NSCLC发生发展，Tyr705磷酸化（pY705-STAT3）水平的高低决定了STAT3活化的程度，是潜在的治疗靶标。泛素化修饰对STAT3调控至关重要，但目前的研究主要关注STAT3本身，而磷酸化STAT3的泛素化与去泛素化调控均未见报道。我们利用去泛素化酶（DUBs）文库筛选，发现去泛素化酶OTUB1能促进NSCLC细胞生长、但依赖STAT3tyr705磷酸化，表明OTUB1可能通过抑制pY705-STAT3泛素化参与NSCLC的疾病进程。在该研究基础上，本项目拟从分子、细胞、动物和临床样本中系统分析OTUB1调控pY705-STAT3去泛素化的分子机制及其在NSCLC发生发展中的作用，为进一步理解NSCLC发病机理、寻找高效治疗靶点提供新的思路和依据。

Non-small cell lung cancer (NSCLC) is a malignant tumor with high morbidity and mortality. It is well established that STAT3 activation can promote the tumorigenesis and development of NSCLC, and is a potential target for the treatment of NSCLC.Tyr705 phosphorylation of the transcription factor STAT3 (pY705-STAT3) is a marker of STAT3 activation. It is well known that the ubiquitination modification is an important mechanism to regulate protein level and stability. However, the regulation of the ubiquitination of phosphorylated STAT3 (pSTAT3) is yet to know. In the preliminary study, we found the deubiquitinase OTUB1 can enhance the transcriptional activity of STAT3 by screening the deubiquitinase library. Surprisingly, OTUB1 enhances the phosphorylation level of STAT3 but has no effect on STAT3 stability. In the functional assay, we found OTUB1 promotes NSCLC cell proliferation in a manner depending on the tyr705 phosphorylation level of STAT3. Therefore, OTUB1 is probably a deubiquitinase of pY705-STAT3, but the detailed mechanisms are yet to know. In the present proposal, we will dissect the detailed mechanisms and biological function of OTUB1-mediated deubiquitination of the phosphorylated STAT3 in NSCLC. This study will help for understanding the pathogenesis of NSCLC as well as provide a novel potential target for the treatment of patients with NSCLC.