黏蛋白1泛素化修饰的动态调控机制及其肿瘤治疗意义研究

黏蛋白1（mucin 1，MUC1）在70%的实体肿瘤中异常高表达，与肿瘤发生、发展及预后不良密切相关。解析MUC1蛋白降解机制将为有效抑制其致瘤功能提供靶点。我们利用数据分析发现MUC1与E3泛素连接酶WWP1在正常组织及多种肿瘤组织中呈负相关；进一步研究发现WWP1泛素化MUC1并使其通过自噬-溶酶体途径降解；敲除WWP1促进肿瘤细胞增殖和肿瘤干细胞增殖，而过表达WWP1则抑制肿瘤细胞增殖。本项目拟在此原创性发现基础上，深入研究WWP1对MUC1泛素化降解的作用；阐明WWP1对MUC1泛素化修饰的动态调控机制；揭示WWP1的调控作用在MUC1高表达肿瘤生长中的生物学功能；寻找激活WWP1-MUC1降解信号通路的药物或小分子化合物。该研究将不仅解析MUC1蛋白动态调控的新机制、获得靶向抑制MUC1功能的新策略，亦可望为临床MUC1阳性肿瘤的早期预防和靶向治疗提供新思路。

Mucin1 (MUC1) is abnormally overexpressed in 70% of solid tumors and is closely related to tumor initiation, development and poor prognosis. Exploring the mechanism of MUC1 protein degradation will provide an effective target for inhibiting its tumorigenic function. Based on dataset analysis, we recently found a negative correlation between MUC1 and an E3 ubiquitin ligase-WWP1 in normal tissues and various tumor tissues. Further studies showed that MUC1 was ubiquitinated and degraded by WWP1 via autophagy-lysosomal pathway. Knockout of WWP1 promoted tumor cell proliferation and spheres formation, while overexpression of WWP1 inhibited tumor cell proliferation. Based on this original discovery, our project intends to further study the effect of WWP1 on ubiquitin-mediated degradation of MUC1; to elucidate the mechanism underlying WWP1 induced ubiquitination and control of the MUC1; to reveal the biological role of WWP1 in controlling proliferation of MUC1-overexpressed tumor cells; to find approaches to activate WWP1 to degrade MUC1. This study will not only clarify the new mechanism of dynamic regulation of MUC1 protein, obtain a new strategy to inhibit MUC1, but also provide novel ideas for the prevention and targeted therapy of MUC1 positive tumors.