泛素化修饰介导的转录因子异常调控在肝癌耐药中的分子机制及治疗策略研究

肝癌的死亡率居高不下，对化疗药物的耐药性是造成这一困境的主要原因之一。转录因子的异常激活是肝癌耐药的关键环节，目前多数研究聚焦于转录因子自身的过度扩增和转录激活，缺乏靶向干预手段。我们研究发现，在肝癌耐药过程中，转录因子的泛素化修饰是其异常激活的重要调控方式，对此进行干预可能成为克服肝癌耐药的全新策略。本项目将系统研究c-Myc、YAP及其它转录因子的异常激活在肝癌耐药中的重要作用，阐明转录因子K48、K27、K29等不同类型的泛素链修饰水平改变对肝癌耐药的影响，并寻找调控该过程的E3泛素连接酶、去泛素化酶等关键泛素修饰酶；进一步以WSB-1、JOSD2等泛素修饰酶为靶点，构建药物筛选模型，发现先导小分子化合物。通过本项目的研究，不仅可阐明泛素化修饰调控转录因子参与肝癌耐药的新分子机制，找到克服肝癌耐药的新策略，还有望开创通过抑制泛素修饰酶而克服转录因子难以靶向干预这一难题的新途径。

Resistance of hepatocellular carcinoma (HCC) to chemotherapeutic agents is a major cause of cancer mortality. The abnormal activation of transcription factors is the key step of drug resistance in HCC. Most of the current researches focus on the over amplification and transcriptional activation of transcription factors. In general, there is still a lack of targeted intervention to target transcription factors. Our study found that ubiquitin modification of transcription factor is an important way to regulate the abnormal activation of HCC, which may become a new strategy to overcome the chemotherapy resistance of HCC. Therefore, this project will systematically study the important role of abnormal activation of c-Myc, YAP and other transcription factors in the chemotherapy resistance of HCC, elucidate the effect of different types (K48, K27, K29 and other types) of ubiquitin chain modification of transcription factors on the drug resistance of HCC, search for the key E3 ubiquitin ligase, deubiquitinating enzymes, which regulate this process. Moreover, we will screen for the pilot small molecule compounds that targeting the E3 ubiquitin ligase, deubiquitinating enzymes such as WSB-1 and JOSD2. Our study will not only clarify the ubiquitination regulatory process of transcription factor involved in chemotherapy resistance of HCC, find new strategies to overcome chemotherapy resistance of HCC, but also find a new intervention to target transcription factors by inhibiting the ubiquitin modification enzymes.