E3泛素连接酶相关非编码RNA调控ERK1/2泛素化促进去势抵抗性前列腺癌的机制研究

E3泛素连接酶活性以及靶蛋白泛素化修饰水平的改变是去势抵抗性前列腺癌（CRPC）发生、发展的重要因素，机制尚不明确。申请者前期研究发现一个新型长链非编码RNA（lncRNA）lnc-MX1-1异常高表达与CRPC密切相关，并且lnc-MX1-1与E3泛素连接酶UBR4有结合位点，而UBR4的底物靶蛋白之一是MAPK/ERK信号通路的重要节点蛋白ERK1/2。据此我们认为：高表达的lnc-MX1-1与UBR4结合能够干扰UBR4的泛素连接酶活性，导致ERK1/2的泛素化降解受到抑制，此机制不仅上调了细胞内ERK1/2蛋白表达水平，而且促进MAPK/ERK信号通路激活，促进CRPC进展。本项目通过分子、细胞、组织和动物等不同层面的实验手段，深入研究E3泛素连接酶相关lnc-MX1-1的功能，构建lnc-MX1-1/UBR4/ERK泛素化调控网络，为揭示CRPC的机制提供新的线索。

Alteration of E3 ubiquitin ligases activity and level of their targets ubiquitination are essential for castration resistance prostate cancer (CRPC) development and progression. However, the mechanism of this process is not clear. We previously found the abnormally high expression of a novel long non-coding RNA (lncRNA) lnc-MX1-1 is closely related to CRPC progression. And lnc-MX1-1 has binding site with E3 ubiquitin ligase UBR4. Additionally, ERK1/2, essential protein in MAPK/ERK signaling pathway, is the target substrate protein of UBR4. Accordingly, we believe that lnc-MX1-1 can interfere UBR4 ubiquitin ligase activity by binding with it, resulting in inhibition of ERK1/2 ubiquitination and degradation. This mechanism not only increases the intracellular ERK1/2 protein level, but also promotes MAPK/ERK signaling pathway activation and CRPC progression. Through this project, we will study and clarify the function of E3 ubiquitin ligases associated lnc-MX1-1 as well as construct lnc-MX1-1/UBR4/ERK regulatory network. More importantly, we hope to provide new clues for revealing the mechanisms of CRPC.