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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.

Titel:	Essential role of MED1 in the transcriptional regulation of ER-dependent oncogenic miRNAs in breast cancer.
Autor/in / Beteiligte Person:	Nagpal, N ; Sharma, S ; Maji, S ; Durante, G ; Ferracin, M ; Thakur, JK ; Kulshreshtha, R
Link:	Full Text Finder (Volltext)
Zeitschrift:	Scientific reports, Jg. 8 (2018-08-07), Heft 1, S. 11805
Veröffentlichung:	London : Nature Publishing Group, copyright 2011-, 2018
Medientyp:	academicJournal
ISSN:	2045-2322 (electronic)
DOI:	10.1038/s41598-018-29546-9
Schlagwort:	Breast Neoplasms genetics Breast Neoplasms pathology Cell Movement genetics Cell Proliferation genetics Estrogen Receptor alpha genetics Female Gene Expression Regulation, Neoplastic Humans MCF-7 Cells Mediator Complex Subunit 1 genetics MicroRNAs genetics Neoplasm Proteins genetics RNA, Neoplasm genetics Response Elements Breast Neoplasms metabolism Estrogen Receptor alpha metabolism Mediator Complex Subunit 1 metabolism MicroRNAs metabolism Neoplasm Proteins metabolism RNA, Neoplasm metabolism Transcription, Genetic
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article; Research Support, Non-U.S. Gov't Language: English [Sci Rep] 2018 Aug 07; Vol. 8 (1), pp. 11805. <i>Date of Electronic Publication: </i>2018 Aug 07. MeSH Terms: Transcription, Genetic* ; Breast Neoplasms / metabolism ; Estrogen Receptor alpha / metabolism ; Mediator Complex Subunit 1 / metabolism ; MicroRNAs / metabolism ; Neoplasm Proteins / metabolism ; RNA, Neoplasm / metabolism ; Breast Neoplasms / genetics ; Breast Neoplasms / pathology ; Cell Movement / genetics ; Cell Proliferation / genetics ; Estrogen Receptor alpha / genetics ; Female ; Gene Expression Regulation, Neoplastic ; Humans ; MCF-7 Cells ; Mediator Complex Subunit 1 / genetics ; MicroRNAs / genetics ; Neoplasm Proteins / genetics ; RNA, Neoplasm / genetics ; Response Elements References: Carcinogenesis. 2012 Apr;33(4):918-30. (PMID: 22345290) ; Proc Natl Acad Sci U S A. 2012 Sep 18;109(38):15330-5. (PMID: 22949648) ; Nucleic Acids Res. 2016 Feb 29;44(4):1591-612. (PMID: 26590257) ; Mol Cell. 1998 Aug;2(2):213-22. (PMID: 9734358) ; EMBO J. 2004 Oct 13;23(20):4051-60. (PMID: 15372072) ; Nat Rev Genet. 2010 Nov;11(11):761-72. (PMID: 20940737) ; Proc Natl Acad Sci U S A. 1999 Sep 14;96(19):10848-53. (PMID: 10485914) ; Annu Rev Biochem. 2000;69:729-49. (PMID: 10966474) ; Cell. 2012 Apr 27;149(3):671-83. (PMID: 22541436) ; Genetics. 2004 Oct;168(2):747-57. (PMID: 15514050) ; Mol Endocrinol. 2006 May;20(5):1073-89. (PMID: 16396960) ; Mol Cell. 1999 Jan;3(1):97-108. (PMID: 10024883) ; RNA. 2017 Aug;23(8):1237-1246. (PMID: 28450532) ; Nat Rev Mol Cell Biol. 2009 Feb;10(2):126-39. (PMID: 19165215) ; Sci Rep. 2015 Apr 13;5:9650. (PMID: 25867965) ; Mol Cell Biol. 2004 Sep;24(18):8244-54. (PMID: 15340084) ; Curr Opin Cell Biol. 2001 Jun;13(3):274-80. (PMID: 11343897) ; Breast Cancer Res. 2010;12(2):201. (PMID: 20346098) ; J Biol Chem. 2008 May 9;283(19):13077-86. (PMID: 18339625) ; Mol Cell Biol. 2005 Mar;25(6):2117-29. (PMID: 15743810) ; Cell. 1994 May 20;77(4):599-608. (PMID: 8187178) ; Mol Cell. 2005 Jul 1;19(1):89-100. (PMID: 15989967) ; Breast Cancer Res. 2011;13(6):R116. (PMID: 22113133) ; Cell. 2013 Apr 11;153(2):307-19. (PMID: 23582322) ; J Biol Chem. 2000 May 19;275(20):14779-82. (PMID: 10747854) ; Mol Cell. 1998 Jul;2(1):43-53. (PMID: 9702190) ; Nat Rev Mol Cell Biol. 2015 Mar;16(3):155-66. (PMID: 25693131) ; Cell. 2013 Jun 6;153(6):1327-39. (PMID: 23746844) ; Yeast. 2001 Sep 15;18(12):1099-110. (PMID: 11536332) ; Carcinogenesis. 2013 Aug;34(8):1889-99. (PMID: 23542418) ; PLoS One. 2012;7(12):e51862. (PMID: 23251644) ; Sci Signal. 2013 Apr 02;6(269):pl1. (PMID: 23550210) ; FASEB J. 2010 Jun;24(6):2030-9. (PMID: 20065103) ; Mol Cell Biol. 2003 Sep;23(17):6229-42. (PMID: 12917344) ; Mol Cell Biol. 2012 Apr;32(8):1483-95. (PMID: 22331469) ; Mol Cell. 2005 Aug 19;19(4):511-22. (PMID: 16109375) ; Mol Cell. 2012 Feb 24;45(4):459-69. (PMID: 22264826) ; Genes Dev. 2001 May 1;15(9):1078-92. (PMID: 11331604) ; Cell. 2011 Jul 8;146(1):92-104. (PMID: 21729782) ; Nat Struct Mol Biol. 2010 Feb;17(2):194-201. (PMID: 20098423) ; Proc Natl Acad Sci U S A. 2002 Mar 5;99(5):2642-7. (PMID: 11867769) ; EMBO Rep. 2010 Jul;11(7):541-7. (PMID: 20508642) ; Cancer Discov. 2012 May;2(5):401-4. (PMID: 22588877) ; PLoS One. 2013 Jul 30;8(7):e70641. (PMID: 23936234) ; Oncotarget. 2015 Feb 10;6(4):2315-30. (PMID: 25537513) ; Epigenetics Chromatin. 2012 Nov 21;5(1):19. (PMID: 23171760) ; Proc Natl Acad Sci U S A. 2003 Oct 14;100(21):12003-8. (PMID: 14506297) ; Mol Cell Biol. 1993 Jan;13(1):63-71. (PMID: 8380229) ; Mol Cell Biol. 2007 Aug;27(15):5306-15. (PMID: 17526732) ; EMBO J. 2002 Jul 1;21(13):3464-75. (PMID: 12093747) ; RNA. 2005 Dec;11(12):1753-61. (PMID: 16314451) ; EMBO J. 2011 Mar 2;30(5):814-22. (PMID: 21252857) ; Gene Expr. 2014;16(2):63-75. (PMID: 24801167) ; PLoS Genet. 2013;9(3):e1003311. (PMID: 23505378) Substance Nomenclature: 0 (ESR1 protein, human) ; 0 (Estrogen Receptor alpha) ; 0 (MED1 protein, human) ; 0 (Mediator Complex Subunit 1) ; 0 (MicroRNAs) ; 0 (Neoplasm Proteins) ; 0 (RNA, Neoplasm) Entry Date(s): Date Created: 20180809 Date Completed: 20191021 Latest Revision: 20210816 Update Code: 20231215 PubMed Central ID: PMC6081450

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