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MiR137 is an androgen regulated repressor of an extended network of transcriptional coregulators

Nilsson, Emeli M.; Laursen, Kristian B.; Whitchurch, Jonathan; McWilliam, Andrew; �dum, Niels; Persson, Jenny L.; Heery, David M.; Gudas, Lorraine G.; Mongan, Nigel P.

MiR137 is an androgen regulated repressor of an extended network of transcriptional coregulators Thumbnail


Authors

Emeli M. Nilsson

Kristian B. Laursen

Jonathan Whitchurch

Andrew McWilliam

Niels �dum

Jenny L. Persson

Profile image of DAVID HEERY

DAVID HEERY david.heery@nottingham.ac.uk
Professor of Eucaryotic Gene Regulation

Lorraine G. Gudas

NIGEL MONGAN nigel.mongan@nottingham.ac.uk
Associate Pro-Vice Chancellorglobal Engagement



Abstract

Androgens and the androgen receptor (AR) play crucial roles in male development and the pathogenesis and progression of prostate cancer (PCa). The AR functions as a ligand dependent transcription factor which recruits multiple enzymatically distinct epigenetic coregulators to facilitate transcriptional regulation in response to androgens. Over-expression of AR coregulators is implicated in cancer. We have shown that over-expression of KDM1A, an AR coregulator, contributes to PCa recurrence by promoting VEGFA expression. However the mechanism(s) whereby AR coregulators are increased in PCa remain poorly understood. In this study we show that the microRNA hsa-miR-137 (miR137) tumor suppressor regulates expression of an extended network of transcriptional coregulators including KDM1A/LSD1/AOF1, KDM2A/JHDM1A/FBXL11, KDM4A/JMJD2A, KDM5B JARID1B/PLU1, KDM7A/JHDM1D/PHF8, MED1/TRAP220/DRIP205 and NCoA2/SRC2/TIF2. We show that expression of miR137 is increased by androgen in LnCaP androgen PCa responsive cells and that the miR137 locus is epigenetically silenced in androgen LnCaP:C4-2 and PC3 independent PCa cells. In addition, we found that restoration of miR137 expression down-regulates expression of VEGFA, an AR target gene, which suggests a role of miR137 loss also in cancer angiogenesis. Finally we show functional inhibition of miR137 function enhanced androgen induction of PSA/KLK3 expression. Our data indicate that miR137 functions as an androgen regulated suppressor of androgen signaling by modulating expression of an extended network of transcriptional coregulators. Therefore, we propose that epigenetic silencing of miR137 is an important event in promoting androgen signaling during prostate carcinogenesis and progression.

Citation

Nilsson, E. M., Laursen, K. B., Whitchurch, J., McWilliam, A., Ødum, N., Persson, J. L., …Mongan, N. P. (2015). MiR137 is an androgen regulated repressor of an extended network of transcriptional coregulators. Oncotarget, 6(34), 35710-35725. https://doi.org/10.18632/oncotarget.5958

Journal Article Type Article
Acceptance Date Sep 12, 2015
Online Publication Date Oct 5, 2015
Publication Date Nov 3, 2015
Deposit Date Oct 12, 2015
Publicly Available Date Oct 12, 2015
Journal Oncotarget
Electronic ISSN 1949-2553
Publisher Impact Journals
Peer Reviewed Peer Reviewed
Volume 6
Issue 34
Pages 35710-35725
DOI https://doi.org/10.18632/oncotarget.5958
Keywords epigenetic, prostate, nuclear receptor, metastases, gleason grade
Public URL https://nottingham-repository.worktribe.com/output/764589
Publisher URL http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path[]=5958

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