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Context dependent regulatory patterns of the androgen receptor and androgen receptor target genes

BACKGROUND: Expression of the androgen receptor (AR) is associated with androgen-dependent proliferation arrest and terminal differentiation of normal prostate epithelial cells. Additionally, activation of the AR is required for survival of benign luminal epithelial cells and primary cancer cells, t...

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Autores principales: Olsen, Jan Roger, Azeem, Waqas, Hellem, Margrete Reime, Marvyin, Kristo, Hua, Yaping, Qu, Yi, Li, Lisha, Lin, Biaoyang, Ke, XI- Song, Øyan, Anne Margrete, Kalland, Karl- Henning
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4932678/
https://www.ncbi.nlm.nih.gov/pubmed/27378372
http://dx.doi.org/10.1186/s12885-016-2453-4
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author Olsen, Jan Roger
Azeem, Waqas
Hellem, Margrete Reime
Marvyin, Kristo
Hua, Yaping
Qu, Yi
Li, Lisha
Lin, Biaoyang
Ke, XI- Song
Øyan, Anne Margrete
Kalland, Karl- Henning
author_facet Olsen, Jan Roger
Azeem, Waqas
Hellem, Margrete Reime
Marvyin, Kristo
Hua, Yaping
Qu, Yi
Li, Lisha
Lin, Biaoyang
Ke, XI- Song
Øyan, Anne Margrete
Kalland, Karl- Henning
author_sort Olsen, Jan Roger
collection PubMed
description BACKGROUND: Expression of the androgen receptor (AR) is associated with androgen-dependent proliferation arrest and terminal differentiation of normal prostate epithelial cells. Additionally, activation of the AR is required for survival of benign luminal epithelial cells and primary cancer cells, thus androgen deprivation therapy (ADT) leads to apoptosis in both benign and cancerous tissue. Escape from ADT is known as castration-resistant prostate cancer (CRPC). In the course of CRPC development the AR typically switches from being a cell-intrinsic inhibitor of normal prostate epithelial cell proliferation to becoming an oncogene that is critical for prostate cancer cell proliferation. A clearer understanding of the context dependent activation of the AR and its target genes is therefore desirable. METHODS: Immortalized human prostate basal epithelial EP156T cells and progeny cells that underwent epithelial to mesenchymal transition (EMT), primary prostate epithelial cells (PrECs) and prostate cancer cell lines LNCaP, VCaP and 22Rv1 were used to examine context dependent restriction and activation of the AR and classical target genes, such as KLK3. Genome-wide gene expression analyses and single cell protein analyses were applied to study the effect of different contexts. RESULTS: A variety of growth conditions were tested and found unable to activate AR expression and transcription of classical androgen-dependent AR target genes, such as KLK3, in prostate epithelial cells with basal cell features or in mesenchymal type prostate cells. The restriction of androgen- and AR-dependent transcription of classical target genes in prostate basal epithelial cells was at the level of AR expression. Exogenous AR expression was sufficient for androgen-dependent transcription of AR target genes in prostate basal epithelial cells, but did not exert a positive feedback on endogenous AR expression. Treatment of basal prostate epithelial cells with inhibitors of epigenetic gene silencing was not efficient in inducing androgen-dependent transcription of AR target genes, suggesting the importance of missing cofactor(s). CONCLUSIONS: Regulatory mechanisms of AR and androgen-dependent AR target gene transcription are insufficiently understood and may be critical for prostate cancer initiation, progression and escape from standard therapy. The present model is useful for the study of context dependent activation of the AR and its transcriptome. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12885-016-2453-4) contains supplementary material, which is available to authorized users.
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spelling pubmed-49326782016-07-06 Context dependent regulatory patterns of the androgen receptor and androgen receptor target genes Olsen, Jan Roger Azeem, Waqas Hellem, Margrete Reime Marvyin, Kristo Hua, Yaping Qu, Yi Li, Lisha Lin, Biaoyang Ke, XI- Song Øyan, Anne Margrete Kalland, Karl- Henning BMC Cancer Research Article BACKGROUND: Expression of the androgen receptor (AR) is associated with androgen-dependent proliferation arrest and terminal differentiation of normal prostate epithelial cells. Additionally, activation of the AR is required for survival of benign luminal epithelial cells and primary cancer cells, thus androgen deprivation therapy (ADT) leads to apoptosis in both benign and cancerous tissue. Escape from ADT is known as castration-resistant prostate cancer (CRPC). In the course of CRPC development the AR typically switches from being a cell-intrinsic inhibitor of normal prostate epithelial cell proliferation to becoming an oncogene that is critical for prostate cancer cell proliferation. A clearer understanding of the context dependent activation of the AR and its target genes is therefore desirable. METHODS: Immortalized human prostate basal epithelial EP156T cells and progeny cells that underwent epithelial to mesenchymal transition (EMT), primary prostate epithelial cells (PrECs) and prostate cancer cell lines LNCaP, VCaP and 22Rv1 were used to examine context dependent restriction and activation of the AR and classical target genes, such as KLK3. Genome-wide gene expression analyses and single cell protein analyses were applied to study the effect of different contexts. RESULTS: A variety of growth conditions were tested and found unable to activate AR expression and transcription of classical androgen-dependent AR target genes, such as KLK3, in prostate epithelial cells with basal cell features or in mesenchymal type prostate cells. The restriction of androgen- and AR-dependent transcription of classical target genes in prostate basal epithelial cells was at the level of AR expression. Exogenous AR expression was sufficient for androgen-dependent transcription of AR target genes in prostate basal epithelial cells, but did not exert a positive feedback on endogenous AR expression. Treatment of basal prostate epithelial cells with inhibitors of epigenetic gene silencing was not efficient in inducing androgen-dependent transcription of AR target genes, suggesting the importance of missing cofactor(s). CONCLUSIONS: Regulatory mechanisms of AR and androgen-dependent AR target gene transcription are insufficiently understood and may be critical for prostate cancer initiation, progression and escape from standard therapy. The present model is useful for the study of context dependent activation of the AR and its transcriptome. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12885-016-2453-4) contains supplementary material, which is available to authorized users. BioMed Central 2016-07-04 /pmc/articles/PMC4932678/ /pubmed/27378372 http://dx.doi.org/10.1186/s12885-016-2453-4 Text en © The Author(s). 2016 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Olsen, Jan Roger
Azeem, Waqas
Hellem, Margrete Reime
Marvyin, Kristo
Hua, Yaping
Qu, Yi
Li, Lisha
Lin, Biaoyang
Ke, XI- Song
Øyan, Anne Margrete
Kalland, Karl- Henning
Context dependent regulatory patterns of the androgen receptor and androgen receptor target genes
title Context dependent regulatory patterns of the androgen receptor and androgen receptor target genes
title_full Context dependent regulatory patterns of the androgen receptor and androgen receptor target genes
title_fullStr Context dependent regulatory patterns of the androgen receptor and androgen receptor target genes
title_full_unstemmed Context dependent regulatory patterns of the androgen receptor and androgen receptor target genes
title_short Context dependent regulatory patterns of the androgen receptor and androgen receptor target genes
title_sort context dependent regulatory patterns of the androgen receptor and androgen receptor target genes
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4932678/
https://www.ncbi.nlm.nih.gov/pubmed/27378372
http://dx.doi.org/10.1186/s12885-016-2453-4
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