Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education, College of Biotechnology, Tianjin University of Science and Technology, Tianjin 300457, China; Tianjin Key Laboratory of Industrial Microbiology, Tianjin 300457, China.
Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education, College of Biotechnology, Tianjin University of Science and Technology, Tianjin 300457, China; Tianjin Key Laboratory of Industrial Microbiology, Tianjin 300457, China.
Cancer Lett. 2014 Mar 1;344(1):129-137. doi: 10.1016/j.canlet.2013.10.026. Epub 2013 Nov 1.
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.
肌球蛋白相关转录因子 A（MRTF-A）是 Rho 信号应答的血清反应因子（SRF）的转录共激活因子。最近的研究表明，MRTF-A 可能是乳腺的重要调节因子，并参与癌症转移。然而，组蛋白修饰在 MRTF-A 依赖性信号通路和肿瘤迁移中的作用尚不清楚。在这里，我们报告组蛋白甲基化是 MRTF-A 介导的肌球蛋白调节轻链 9（MYL9）上调所必需的，MYL9 是一种重要的细胞骨架成分，与细胞迁移有关。此外，我们证明 SET 和 MYND 结构域包含蛋白 3（SMYD3），一种与致癌作用相关的组蛋白甲基转移酶（HMT），可能是负责 MRTF-A 介导的 MYL9 转录激活和乳腺癌细胞迁移中组蛋白甲基化的酶。SMYD3 的过表达促进 MCF-7 乳腺癌细胞中 MRTF-A 介导的 MYL9 上调和迁移，而当用特异性 siRNA 抑制内源性 MRTF-A 和 SMYD3 时则观察到相反的结果。此外，突变分析表明，这种协同转录激活主要是通过 MYL9 启动子中 MRTF-A 的近端结合元件介导的，并且需要 SMYD3 的 HMT 活性。我们的发现揭示了 MRTF-A 和 SMYD3 在转录调控和细胞迁移中的作用的新机制，并为乳腺癌的转移提供了更好的理解。
