Automethylation of protein arginine methyltransferase 7 and its impact on breast cancer progression
Automethylation of protein arginine methyltransferase 7 and its impact on breast cancer progression
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蛋白质精氨酸甲基转移酶7的自甲基化及其对乳腺癌进展的影响
DOI：
10.1096/fj.201601196r
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发表时间：
2017-06-01
期刊：
影响因子：
4.8
通讯作者：
Lu, Jun
中科院分区：
文献类型：
--
作者：
Geng, Pengyu;Zhang, Yu;Lu, Jun
蛋白质精氨酸甲基转移酶（PRMT）催化蛋白质精氨酸甲基化，并与癌的发生和转移有关。已发现PRMT的一些成员进行自甲基化;然而，这种自我修饰的生物学意义尚不完全清楚。在这份报告中，我们证明了PRMT 7的R531在体外和体内都是自甲基化的。PRMT 7的自甲基化在诱导上皮-间质转化（EMT）程序和促进乳腺癌细胞的迁移和侵袭行为中起关键作用。我们还在裸鼠模型中证明了野生型PRMT 7在MCF 7乳腺癌细胞中的表达促进了体内转移，与PRMT 7 R531 K突变体（未甲基化状态的模拟物）相反。此外，我们的免疫组化数据揭示了PRMT 7自甲基化与乳腺癌临床结果之间的密切联系。从机制上讲，我们确定PRMT 7自甲基化的丧失导致YY 1对E-钙粘蛋白启动子的招募减少，从而通过降低H4 R3 me 2s水平来解除E-钙粘蛋白表达的抑制。这项工作中的发现定义了PRMT 7的一种新的翻译后修饰，其对乳腺癌转移具有促进作用。
Protein arginine methyltransferases (PRMTs) catalyze protein arginine methylation and are linked to carcinogenesis and metastasis. Some members of PRMTs have been found to undergo automethylation; however, the biologic significance of this self-modification is not entirely clear. In this report, we demonstrate that R531 of PRMT7 is self-methylated, both in vitro and in vivo. Automethylation of PRMT7 plays a key role in inducing the epithelial-mesenchymal transition (EMT) program and in promoting the migratory and invasive behavior of breast cancer cells. We also prove in a nude mouse model that expression of wild-type PRMT7 in MCF7 breast cancer cells promotes metastasis in vivo, in contrast to the PRMT7 R531K mutant (a mimic of the unmethylated status). Moreover, our immunohistochemical data unravel a close link between PRMT7 automethylation and the clinical outcome of breast carcinomas. Mechanistically, we determine that loss of PRMT7 automethylation leads to the reduction of its recruitment to the E-cadherin promoter by YY1, which consequently derepresses the E-cadherin expression through decreasing the H4R3me2s level. The findings in this work define a novel post-translational modification of PRMT7 that has a promoting impacton breast cancer metastasis.