Abstract
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.
Highlights
Mediator is an evolutionary conserved large multiprotein complex that plays critical role in relaying the regulatory signal from DNA-bound gene-specific transcription factors to the RNA polymerase II transcriptional machinery[1,2,3]
Mediator complex subunit 1 (MED1) mRNA expression levels correlated with the copy number variations (Fig. 1B) and is significantly higher in ER+ and ER- breast cancer compared to normal breast (Supplementary Data 1A,B)
We found that breast cancer patients with higher MED1 levels had poor survival than patients with low MED1 levels with the results being more significant for the ER+ patients (Fig. 1C)
Summary
Mediator is an evolutionary conserved large multiprotein complex that plays critical role in relaying the regulatory signal from DNA-bound gene-specific transcription factors to the RNA polymerase II transcriptional machinery[1,2,3]. In Arabidopsis, a set of Mediator subunits is involved in the transcription of ncRNAs that helps in recruitment of RNA pol V, a plant-specific polymerase evolved from Pol II15. In Arabidopsis, Mediator has been shown to be involved in miRNA biogenesis by recruiting RNA Pol II to the promoters of miRNA genes[15]. MiRNA genes are transcribed by RNA Pol II in metazoans[19], the direct involvement of Mediator complex in the regulation of miRNA expression in metazoans has not been shown. We show that estrogen (E2)-activated ER-α targets MED1 to recruit Mediator complex to the promoter of miR-191/425 cluster inducing their transcription. Both miR-191 and MED1 promote breast cancer cell proliferation and migration. MED1 is shown here to be involved in the regulation of other breast cancer related miRNAs suggesting the crucial and yet unexplored role of Mediator complex in breast cancer pathogenesis through regulation of miRNAs
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