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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; Ødum, Niels; Persson, Jenny L.; Heery, David M.; Gudas, Lorraine G.; Mongan, Nigel P.

Authors

Emeli M. Nilsson

Kristian B. Laursen

Jonathan Whitchurch

Andrew McWilliam

Niels Ødum

Jenny L. Persson

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

Lorraine G. Gudas



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.

Journal Article Type Article
Publication Date Nov 3, 2015
Journal Oncotarget
Electronic ISSN 1949-2553
Publisher Impact Journals
Peer Reviewed Peer Reviewed
Volume 6
Issue 34
APA6 Citation Gudas, L. J., Nilsson, E. M., Laursen, K. B., Whitchurch, J., McWilliam, A., Ødum, N., …Mongan, N. P. (2015). MiR137 is an androgen regulated repressor of an extended network of transcriptional coregulators. Oncotarget, 6(34), https://doi.org/10.18632/oncotarget.5958
DOI https://doi.org/10.18632/oncotarget.5958
Keywords epigenetic, prostate, nuclear receptor, metastases, gleason grade
Publisher URL http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path[]=5958
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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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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