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Essential role of MED1 in the transcriptional regulation of ER-dependent oncogenic miRNAs in breast cancer

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Title Essential role of MED1 in the transcriptional regulation of ER-dependent oncogenic miRNAs in breast cancer
 
Creator Nagpal, Neha
Sharma, Shivani
Maji, Sourobh
Durante, Giorgio
Ferracin, Manuela
Thakur, Jitendra K.
Kulshreshtha, Ritu
 
Subject Mediator complex
breast cancer
transcriptional regulation
oncogenic miRNAs
 
Description Accepted date: 12 July 2018
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.
This work was supported by the grant [SB/SO/BB/088/2013] from Science and Engineering Research Board, Department of Science & Technology, Government of India to RK and grant [BT/PR14519/BRB/10/869/2010] by Department of Biotechnology, Government of India and NIPGR core grant to JKT. NN and SS thank Centre for Scientific and Industrial Research for Senior Research Fellowship. SM thanks University Grants Commission for Senior Research Fellowship.
 
Date 2018-08-16T10:06:43Z
2018-08-16T10:06:43Z
2018
 
Type Article
 
Identifier Scientific Reports, 8(1): 11805
2045-2322
http://223.31.159.10:8080/jspui/handle/123456789/878
https://www.nature.com/articles/s41598-018-29546-9
10.1038/s41598-018-29546-9
 
Language en_US
 
Format application/pdf
 
Publisher Springer Nature