PRMT7 Induces Epithelial-to-Mesenchymal Transition and Promotes Metastasis in Breast Cancer
PRMT7 Induces Epithelial-to-Mesenchymal Transition and Promotes Metastasis in Breast Cancer
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PRMT7 诱导上皮间质转化并促进乳腺癌转移
DOI：
10.1158/0008-5472.can-14-0800
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发表时间：
2014-10-01
期刊：
影响因子：
11.2
通讯作者：
Lu, Jun
中科院分区：
文献类型：
--
作者：
Yao, Ruosi;Jiang, Hao;Lu, Jun
上皮-间质转化（EMT）使转移成为可能。E-cadherin丢失是EMT的一个标志，但对这一过程的表观遗传学仍有不完整的理解。蛋白质精氨酸甲基转移酶PRMT 7在各种生理过程中起作用，包括mRNA剪接、DNA修复和神经分化，但其在癌症和转移中的可能作用尚未被探索。在这份报告中，我们发现PRMT 7在乳腺癌细胞中以更高的水平表达，并且PRMT 7的升高介导了EMT和转移。PRMT 7可以通过以与改变的组蛋白甲基化相关的方式结合其近端启动子来抑制E-钙粘蛋白的表达，特别是与升高的H4 R3 me 2s和降低的H3 K4 me 3、H3 Ac和H4 Ac相关，这在EMT诱导后发生在E-钙粘蛋白启动子处。此外，PRMT 7与YY 1和HDAC 3相互作用，并且是将这些蛋白质连接到E-钙粘蛋白启动子所必需的。沉默PRMT 7通过抑制H4 R3 me 2s并通过增加H3 K4 me 3和H4 Ac恢复E-钙粘蛋白表达，减弱MDA-MB-231乳腺癌细胞中的细胞迁移和侵袭。总的来说，我们的研究结果将PRMT 7定义为乳腺癌转移的诱导物，并为应用PRMT 7靶向疗法治疗高度侵袭性乳腺癌提供了机会。(C)2014年AACR。
Epithelial-to-mesenchymal transition (EMT) enables metastasis. E-cadherin loss is a hallmark of EMT, but there remains an incomplete understanding of the epigenetics of this process. The protein arginine methyltransferase PRMT7 functions in various physiologic processes, including mRNA splicing, DNA repair, and neural differentiation, but its possible roles in cancer and metastasis have not been explored. In this report, we show that PRMT7 is expressed at higher levels in breast carcinoma cells and that elevated PRMT7 mediates EMT and metastasis. PRMT7 could inhibit the expression of E-cadherin by binding to its proximal promoter in a manner associated with altered histone methylation, specifically with elevated H4R3me2s and reduced H3K4me3, H3Ac, and H4Ac, which occurred at the E-cadherin promoter upon EMT induction. Moreover, PRMT7 interacted with YY1 and HDAC3 and was essential to link these proteins to the E-cadherin promoter. Silencing PRMT7 restored E-cadherin expression by repressing H4R3me2s and by increasing H3K4me3 and H4Ac, attenuating cell migration and invasion in MDA-MB-231 breast cancer cells. Overall, our results define PRMT7 as an inducer of breast cancer metastasis and present the opportunity for applying PRMT7-targeted therapeutics to treat highly invasive breast cancers. (C) 2014 AACR.