USP28介导的FOXK1去泛素化激活Hippo信号通路调控肺癌放疗敏感性的研究

转录因子FOXK1能调控细胞DNA双链断裂修复，但其与肺癌放疗敏感性的关系及上下游调控的分子机制仍需进一步阐明。申请人研究发现：FOXK1在肺癌细胞系中高表达，且能促进肺癌细胞增殖和放射抵抗。预实验结果显示去泛素化酶USP28与FOXK1相互作用并调控其蛋白稳定性和泛素化水平，提示FOXK1是USP28的去泛素化底物分子；沉默FOXK1后，Hippo信号通路中YAP1、TAZ及TEAD1的表达水平均显著下调。因此，我们推测：FOXK1与USP28结合并发生去泛素化，从而激活Hippo信号通路，最终促进肺癌放疗抵抗。本项目拟明确FOXK1在肺癌中的表达情况，并分析其临床预后意义；阐明FOXK1在肺癌放疗抵抗中的作用；探究FOXK1在USP28的作用下发生去泛素化修饰，并进一步调控下游Hippo信号通路的分子机制。本研究的完成有望阐明肺癌放疗抵抗新的分子机制，为肺癌放疗增敏提供新的分子靶点。

Transcription factor FOXK1 has been reported to regulate DNA double-strand break repair. However, the role of FOXK1 in lung cancer radiosensitivity and the molecular mechanism how FOXK1 is regulated remain unclear. The preliminary data show that FOXK1 is highly expressed in lung cancer cells and promotes lung cancer cell proliferation and radioresistance. Deubiquitinase USP28 can interact with FOXK1 and regulate FOXK1 protein stability and ubiquitination level, suggesting that FOXK1 is a candidate deubiquitination substrate of USP28. In addition, FOXK1 silencing significantly decreases the expression level of YAP1, TAZ and TEAD1 in the Hippo signaling pathway. Therefore, we propose that USP28 interacts with FOXK1 and mediates its deubiquitination and stabilization, subsequently activating the Hippo signaling pathway, ultimately leading to radioresistance in lung cancer. In this study, we will determine the expression level of FOXK1 in lung cancer tissues and analyze its clinical prognostic value, then clarify the role of FOXK1 in lung cancer radioresistance, and further elucidate the molecular mechanism that USP28-mediated deubiquitination of FOXK1 activates Hippo signaling pathway. This study may clarify the new molecular mechanism of radioresistance and provide a potential target for radiosensitization in lung cancer.