Histone methyltransferase SMYD3 promotes MRTF-A-mediated transactivation of MYL9 and migration of MCF-7 breast cancer cells
Histone methyltransferase SMYD3 promotes MRTF-A-mediated transactivation of MYL9 and migration of MCF-7 breast cancer cells
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组蛋白甲基转移酶SMYD3促进MRTF-A介导的MYL9反式激活和MCF-7乳腺癌细胞的迁移
DOI：
10.1016/j.canlet.2013.10.026
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发表时间：
2014-03-01
期刊：
影响因子：
9.7
通讯作者：
Zhang, Tong-Cun
中科院分区：
文献类型：
--
作者：
Luo, Xue-Gang;Zhang, Chun-Ling;Zhang, Tong-Cun
心肌钙蛋白相关转录因子-A(MRTF-A)是血清反应因子(SRF)的Rho信号反应性转录共激活因子。最近的研究表明，MRTF-A可能是一种重要的乳腺调节因子，参与肿瘤的转移。然而，组蛋白修饰在MRTF-A依赖的信号通路和肿瘤迁移中的作用仍不是很清楚。在此，我们报道了组蛋白甲基化是MRTF-A介导的肌球蛋白调节轻链9(MYL9)上调所必需的，MYL9是与细胞迁移有关的重要细胞骨架成分。此外，我们还证明了SET和MyND结构域包含蛋白3(SMYD3)是一种与癌变相关的甲基转移酶(HMT)，它可能是MRTF-A介导的MYL9反式激活和乳腺癌细胞迁移过程中发生组蛋白甲基化的原因。SMYD3过表达促进了MRTF-A介导的MYL9上调和MCF-7乳腺癌细胞的迁移，而内源性MRTF-A和SMYD3被特异性siRNAs抑制则相反。此外，突变分析表明，这种协同反式激活主要是通过MYL9启动子中MRTF-A的近端结合元件介导的，SMYD3的HMT活性也是必需的。我们的发现揭示了MRTF-A和SMYD3在转录调控和细胞迁移中发挥作用的新机制，并为更好地了解乳腺癌的转移提供了更好的认识。(C)2013爱思唯尔爱尔兰有限公司。保留所有权利。
Myocardin-related transcription factor-A (MRTF-A) is a Rho signal-responsive transcriptional coactivator of serum response factor (SRF). Recent studies indicated that MRTF-A might be an important regulator of mammary gland and be involved in cancer metastasis. However, the roles of histone modification in the MRTF-A-dependent signal pathway and tumor migration are still not very clear. Here, we report that histone methylation is required for the MRTF-A-mediated upregulation of myosin regulatory light chain 9 (MYL9), an important cytoskeletal component which is implicated in cell migration. Furthermore, we demonstrate that SET and MYND domain containing protein 3 (SMYD3), a hitone methyltransferase (HMT) associated with carcinogenesis, might be the one which is responsible for the histone methylation occurred in the MRTF-A-mediated- transactivation of MYL9 and migration of breast cancer cells. Overexpression of SMYD3 promotes MRTF-A-mediated upregulation of MYL9 and migration of MCF-7 breast cancer cells, while contrary results were observed when the endogenous MRTF-A and SMYD3 were suppressed with specific siRNAs. In addition, the mutation analysis suggested that this cooperative transactivation is mainly mediated via the proximal binding element of MRTF-A in the promoter of MYL9, and the HMT activity of SMYD3 is required as well. Our findings reveal a new mechanism by which MRTF-A and SMYD3 functions in transcriptional regulation and cell migration, and provide a better understanding for metastasis of breast cancer. (C) 2013 Elsevier Ireland Ltd. All rights reserved.