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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 LU ; Heery, David M; Gudas, Lorraine J and Mongan, Nigel P (2015) In Oncotarget 6(34). p.35710-35725
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... (More)
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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Oncotarget
volume
6
issue
34
pages
35710 - 35725
publisher
Impact Journals, LLC
external identifiers
  • pmid:26461474
  • wos:000366111900055
  • scopus:84946882045
ISSN
1949-2553
DOI
10.18632/oncotarget.5958
language
English
LU publication?
yes
id
4109e43f-180c-4014-bd5e-024d63f5c73a (old id 8152488)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/26461474?dopt=Abstract
date added to LUP
2015-11-03 12:07:07
date last changed
2017-08-06 03:57:39
@article{4109e43f-180c-4014-bd5e-024d63f5c73a,
  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.},
  author       = {Nilsson, Emeli M and Laursen, Kristian B and Whitchurch, Jonathan and McWilliam, Andrew and Ødum, Niels and Persson, Jenny L and Heery, David M and Gudas, Lorraine J and Mongan, Nigel P},
  issn         = {1949-2553},
  language     = {eng},
  number       = {34},
  pages        = {35710--35725},
  publisher    = {Impact Journals, LLC},
  series       = {Oncotarget},
  title        = {MIR137 is an androgen regulated repressor of an extended network of transcriptional coregulators.},
  url          = {http://dx.doi.org/10.18632/oncotarget.5958},
  volume       = {6},
  year         = {2015},
}