PRMT5促进宫颈癌EMT及转移的表观遗传调控机制的研究

PRMT5 is a type II arginine methyltransferase that has been reported to take part in gene silencing regulation through symmetrically dimethylation of histone including H4R3, H3R8 and H3R2. In addition, PRMT5 can participate in multiple cellular processes, including cell proliferation, DNA replication, cell cycle, and cell invasion and metastasis through binding to a variety of epigenetic regulators and complexes and regulating the expression of target genes. However, the relation between PRMT5 and cervical cancer metastasis and the regulation of CSC is still unknown. Our preliminary results showe that PRMT5 can interacte with Snail and the NuRD complex, and promote the invasion and metastasis of cervical cancer cells. Based on the work, our research will discover the molecular mechanism of PRMT5 coordinated with Snail and the NuRD complex in gene regulation by MS, co-IP, ChIP-Seq, IVIS and so on. This project will help us to better understand the role of PRMT5 in tumor progression, and provide insights of new targets for the diagnosis and therapy of cervical cancer.

PRMT5是一种II类精氨酸甲基转移酶，能够催化蛋白质精氨酸对称性二甲基化。研究发现PRMT5能够催化组蛋白H4R3、H3R8和H3R2等位点的对称性二甲基化，参与基因的转录抑制；此外，PRMT5还可以与多种表观遗传调控复合物结合，通过调节靶基因的表达参与到细胞增殖、DNA复制、细胞周期等多个细胞进程中。但PRMT5参与宫颈癌EMT及转移和肿瘤干细胞调控的表观遗传学机制目前并不清楚。我们的初步实验结果表明，PRMT5能够与Snail和NuRD复合物相互作用，并能够促进宫颈癌细胞的迁移、侵袭和宫颈癌肿瘤干细胞的成瘤能力。本研究旨在此工作的基础之上，通过免疫亲和纯化质谱、免疫共沉淀、ChIP-Seq和小动物活体成像等方式探索PRMT5参与基因表观遗传调控的分子机制，发现其与Snail和NuRD复合物协同调控的靶基因，明确其在宫颈癌转移和CSC调控中的作用，最终揭示其生理病理学功能。

PRMT5是II类精氨酸甲基转移酶家族（PRMT家族）成员，可以催化对称性二甲基化。PRMT5可以通过催化H4R3和H3R8等的组蛋白对称性二甲基化参与基因的转录抑制调控。PRMT5可通过与多种表观调控因子结合调控靶基因的转录，它的转录抑制作用参与到包括增殖、DNA复制、细胞周期和细胞侵袭迁移等的多种细胞进程中。但是在宫颈癌中PRMT5的作用及其作用机制尚待进一步研究。本项目中，我们发现PRMT5可以与转录因子Snail及NuRD(MTA1)复合物有机结合形成一个转录调控复合体，可以调控组蛋白的对称性二甲基化及去乙酰化。Snail/PRMT5/NuRD(MTA1)复合物可以调控TET1和E-cadherin等EMT关键调控因子的转录。该复合物可以调控DNA 5mC向5hmC的转换。该项目通过体内、体外实验证明Snail/PRMT5/NuRD(MTA1)复合物可以促进宫颈癌细胞的侵袭转移，并且PRMT5的小分子抑制剂EPZ015666可以通过去TET1的转录抑制和增加DNA 5hmC有效的抑制宫颈癌的侵袭能力。该项目研究结果进一步证实PRMT5具有成为肿瘤治疗新靶点的潜力。