Emeli M. Nilsson
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.
Authors
Kristian B. Laursen
Jonathan Whitchurch
Andrew McWilliam
Niels �dum
Jenny L. Persson
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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Copyright Statement
Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0
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