Department of Biochemical Engineering and Biotechnology, Indian Institute of Technology Delhi, New Delhi, 110016, India.
Children's Hospital, Harvard Medical School, Boston, MA, USA.
Sci Rep. 2018 Aug 7;8(1):11805. doi: 10.1038/s41598-018-29546-9.
Mediator complex has been extensively shown to regulate the levels of several protein-coding genes; however, its role in the regulation of miRNAs in humans remains unstudied so far. Here we show that MED1, a Mediator subunit in the Middle module of Mediator complex, is overexpressed in breast cancer and is a negative prognostic factor. The levels of several miRNAs (miR-100-5p, -191-5p, -193b-3p, -205-5p, -326, -422a and -425-5p) were found to be regulated by MED1. MED1 induces miR-191/425 cluster in an estrogen receptor-alpha (ER-α) dependent manner. Occupancy of MED1 on estrogen response elements (EREs) upstream of miR-191/425 cluster is estrogen and ER-α-dependent and ER-α-induced expression of these miRNAs is MED1-dependent. MED1 mediates induction of cell proliferation and migration and the genes associated with it (JUN, FOS, EGFR, VEGF, MMP1, and ERBB4) in breast cancer, which is abrogated when used together with miR-191-inhibition. Additionally, we show that MED1 also regulates the levels of direct miR-191 target genes such as SATB1, CDK6 and BDNF. Overall, the results show that MED1/ER-α/miR-191 axis promotes breast cancer cell proliferation and migration and may serve as a novel target for therapy.
中介复合物已被广泛证明可调节几种蛋白质编码基因的水平；然而，迄今为止，其在调节人类 miRNA 方面的作用尚未得到研究。在这里，我们表明中介复合物中间模块的 Mediator 亚基 MED1 在乳腺癌中过表达，并且是一个负预后因素。发现几种 miRNA（miR-100-5p、-191-5p、-193b-3p、-205-5p、-326、-422a 和 -425-5p）的水平受到 MED1 的调节。MED1 以雌激素受体-α (ER-α) 依赖的方式诱导 miR-191/425 簇。MED1 在 miR-191/425 簇上游的雌激素反应元件 (EREs) 上的占据是雌激素和 ER-α 依赖性的，并且这些 miRNA 的 ER-α 诱导表达是依赖于 MED1 的。MED1 介导了乳腺癌中细胞增殖和迁移及其相关基因（JUN、FOS、EGFR、VEGF、MMP1 和 ERBB4）的诱导，当与 miR-191 抑制一起使用时，这种诱导作用被消除。此外，我们还表明，MED1 还调节直接的 miR-191 靶基因（如 SATB1、CDK6 和 BDNF）的水平。总的来说，这些结果表明 MED1/ER-α/miR-191 轴促进了乳腺癌细胞的增殖和迁移，可能成为一种新的治疗靶点。
