REJ-C1G3诱导Brd4降解的机制及其抗肿瘤活性研究

研究表明，Brd4与人类肿瘤的发生密切相关，是肿瘤药物开发的新型靶点。目前已有的Brd4抑制剂存在特异性不足，对其家族成员的选择性不高等问题。我们前期研究结果显示： 中药虎杖活性提取物REJ-C1G3可特异性的诱导Brd4的降解，而不能诱导其家族同源物Brd2、Brd3、BrdT的降解；且该降解可能是通过诱导Brd4的多聚泛素化蛋白水解途径发生的。本项目拟在前期研究基础上，进一步甄别REJ-C1G3诱导Brd4降解的特异性，阐明REJ-C1G3对Brd4的多聚泛素化诱导及其机制，探讨REJ-C1G3靶向Brd4的抗肿瘤活性作用。本项目的开展将有助于Brd4靶向药物的开发和设计，为肿瘤的精准靶向治疗提供新的方向和理论基础。

Accumulating studies have revealed the critical roles of Brd4 in cancer development. It is a novel and promising drug target for cancer therapy. However, Brd4 inhibitors show no specificity and selectivity for individual BET family members. Our Preliminary data suggested REJ-C1G3, a natural product purified from roots of polygonum cuspidatum, specifically cause Brd4 degradation in between BET family members; a specific ubiquitin-proteasome pathway may be activated by REJ-C1G3 to cause Brd4 degradation. In this proposal, we plan to further identify the specificity of REJ-C1G3 induced Brd4 degradation in genome wide, elucidate the molecular mechanism of polyubiquitinated Brd4 degradation caused by REJ-C1G3, explore the anti-tumor function of REJ-C1G3 by targeting Brd4. This project will facilitate the drug design and development by targeting Brd4, provide a new direction and theoretical foundation for accurate anti-tumor treatment.