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

被引：14

作者：

Nagpal, Neha ^{[1
,4
]}

Sharma, Shivani ^{[1
]}

Maji, Sourobh ^{[2
]}

Durante, Giorgio ^{[3
]}

Ferracin, Manuela ^{[3
]}

Thakur, Jitendra K. ^{[2
]}

Kulshreshtha, Ritu ^{[1
]}

机构：

[1] Indian Inst Technol Delhi, Dept Biochem Engn & Biotechnol, New Delhi 110016, India

[2] Natl Inst Plant Genome Res, Aruna Asaf Ali Marg, New Delhi 110067, India

[3] Univ Bologna, Dept Expt Diagnost & Specialty Med DIMES, I-40126 Bologna, Italy

[4] Harvard Med Sch, Childrens Hosp, Boston, MA USA

来源：

SCIENTIFIC REPORTS | 2018年 / 8卷

关键词：

RNA-POLYMERASE-II; SYSTEMIC ENERGY HOMEOSTASIS; RECEPTOR-BINDING PROTEIN; MEDIATOR COMPLEX; COACTIVATOR COMPLEX; NEGATIVE REGULATION; SUBUNIT; MICRORNA; ELONGATION; PROMOTER;

D O I：

10.1038/s41598-018-29546-9

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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-alpha) dependent manner. Occupancy of MED1 on estrogen response elements (EREs) upstream of miR-191/425 cluster is estrogen and ER-alpha-dependent and ER-alpha-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-alpha/miR-191 axis promotes breast cancer cell proliferation and migration and may serve as a novel target for therapy.

引用

页数：14