组蛋白甲基转移酶EZH2的精氨酸甲基化修饰促进乳腺癌转移的作用和机制研究

EZH2 ,as a key component of PRC2 ,is a histone methyltransferase. EZH2 has a great effect on human cancers. EZH2 is highly expression both in breast cancer cell lines and breast cancer tissues, which promotes breast cancer metastasis in patients. Many studies have found the post-translational modification of EZH2 (such as phosphorylation, acetylation, glycosylation and ubiquitination) plays a key role in EZH2 functions during cancer progression. Our previous study have shown that EZH2 is methylated on arginine 342 residue by PRMT1. R342-methylated EZH2 increases its protein stability by inhibiting EZH2 ubiquitin-proteasome degradation. Besides, EZH2-R342 methylation enhances breast cancer cells EMT program. There is not any study about arginine-methylated modification of EZH2 until now.Our project will uncover the function of PRMT1 mediated EZH2-R342 methylation in breast cancer through molecular level, cell lines level and mouse model level. And we will demonstrate the depth mechanism of R342-EZH2 methylation increasing its protein stability. Moreover, we will reveal the correlation between EZH2-R342 methylation and breast cancer metastasis. Finally, new idea and potential objective will be provided for the exploration of breast cancer treatment targets.

EZH2作为PRC2复合物的重要组成亚基，是一个在癌症中发挥重要功能的组蛋白甲基转移酶。EZH2在乳腺癌细胞和组织中均呈现高表达，EZH2增多促进乳腺癌发生侵袭转移。许多研究已经发现EZH2的翻译后修饰（磷酸化、乙酰化、糖基化、泛素化）对其在癌症进程中功能发挥有重要影响。项目申请人前期工作发现：EZH2的第342精氨酸（R342）能够被精氨酸甲基转移酶PRMT1进行甲基化修饰，而且EZH2的R342甲基化修饰能够抑制其泛素化降解，增强EZH2蛋白稳定性，进而促进乳腺癌细胞EMT进程，这些发现尚未见相关研究报道。本研究将分别在分子、细胞和动物模型三个层面上，探讨PRMT1介导的EZH2甲基化修饰在乳腺癌发生发展和转移中的作用；阐明EZH2-R342甲基化修饰增强EZH2蛋白稳定性的详细分子机制；揭示EZH2-R342甲基化修饰和乳腺癌转移的关系。最终为乳腺癌治疗靶标的探索提供新的思路和靶点。

组蛋白甲基化转移酶2（EZH2）是关键的组蛋白甲基转移酶和EMT诱导因子，在乳腺癌等多种肿瘤中过表达；但肿瘤中EZH2表达失调的分子机制仍未知。在此，我们发现PRMT1催化EZH2的R342位点发生非对称二甲基化修饰形成（meR342-EZH2）；并且发现meR342-EZH2可以抑制CDK1介导EZH2 的T345和T487磷酸化，从而通过E3连接酶TRAF6衰减EZH2泛素化。我们也进一步证实了meR342-EZH2导致EZH2靶基因表达减少，乳腺癌细胞EMT和迁移侵袭增加。此外，我们还证实了乳腺癌组织中PRMT1、meR342-EZH2与EZH2三者表达之间存在正相关。最后，我们发现乳腺癌患者中meR342-EZH2高表达和乳腺癌患者临床不良预后正相关。我们的发现可能为乳腺癌转移提供了新的诊断靶点和潜在的治疗靶点。