CSN6/Snail1通路调控上皮间质转化及其在前列腺癌进展中的作用

CSN6可增强MDM2稳定性，过表达MDM2可促进肿瘤转移，但CSN6与肿瘤转移关系及分子机制未见报道；本研究显示，CSN6可诱导前列腺癌细胞(PCa)发生EMT，同时上调MDM2。研究表明，MDM2为泛素E3连接酶，通过调控靶蛋白降解发挥其功能；Foxo3a是MDM2底物蛋白，抑制Foxo3a可诱导癌细胞发生EMT；Snail1能抑制E-cadherin转录并启动EMT。本研究显示，PCa细胞中过表达CSN6，Foxo3a表达下调，Snail1表达升高； 通过JASPAR数据库，发现Snail1启动子区存在Foxo3a结合位点。因此我们推测CSN6是PCa细胞EMT发生的重要调节分子，通过稳定MDM2，下调Foxo3a表达，进而降低其对Snail1的转录抑制，Snail1表达升高，下调E-cadherin，诱导EMT，最终促进细胞侵袭和转移。上述机制如证实，将为PCa治疗提供新靶点。

CSN6 can stabilized MDM2, overexpression of MDM2 can promote the tumor metastasis. But the relationship and the underlying mechanism between CSN6 and tumor metastasis is unclear. The present study show that CSN6 induce EMT in PCa DU145 cells, and up regulates the expression of MDM2. Another report show that regulation of the degradation of target protein is the valide way to execute the biological function of E3 ligase MDM2. Foxo3a is a target proteion of MDM2. Repress the expression of Foxo3a can induce EMT in cancer cells. Sanil can promote EMT through directly repress the transcription of E-cadherin. In this study, we report, there is downregulated expression of Foxo3a and upregulated expression of Snail in CSN6-overexpressed cells. By JASPAR database, Foxo3a binding sites in the Snail1 promoter were detected. Therefore, We will identify CSN6 functions as a regulator of EMT in PCa cells. CSN6 can induce EMT via stablizing MDM2, down-regulating the expression of Foxo3a, the inhibation of the transcription of Snail1 was decreased, up-regulating the snail1, then repress the expression of E-cadherin, at last promote EMT and cell invasion in PCa cells. The hypothesis will also be investigated in animal experiment and human prostate cancer tissues. If it is verified, our study may provide a new target for prostate.