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The histone demethylase enzyme KDM3A is a key estrogen receptor regulator in breast cancer

Endocrine therapy has successfully been used to treat estrogen receptor (ER)-positive breast cancer, but this invariably fails with cancers becoming refractory to treatment. Emerging evidence has suggested that fluctuations in ER co-regulatory protein expression may facilitate resistance to therapy...

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Autores principales: Wade, Mark A., Jones, Dominic, Wilson, Laura, Stockley, Jacqueline, Coffey, Kelly, Robson, Craig N., Gaughan, Luke
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4288188/
https://www.ncbi.nlm.nih.gov/pubmed/25488809
http://dx.doi.org/10.1093/nar/gku1298
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author Wade, Mark A.
Jones, Dominic
Wilson, Laura
Stockley, Jacqueline
Coffey, Kelly
Robson, Craig N.
Gaughan, Luke
author_facet Wade, Mark A.
Jones, Dominic
Wilson, Laura
Stockley, Jacqueline
Coffey, Kelly
Robson, Craig N.
Gaughan, Luke
author_sort Wade, Mark A.
collection PubMed
description Endocrine therapy has successfully been used to treat estrogen receptor (ER)-positive breast cancer, but this invariably fails with cancers becoming refractory to treatment. Emerging evidence has suggested that fluctuations in ER co-regulatory protein expression may facilitate resistance to therapy and be involved in breast cancer progression. To date, a small number of enzymes that control methylation status of histones have been identified as co-regulators of ER signalling. We have identified the histone H3 lysine 9 mono- and di-methyl demethylase enzyme KDM3A as a positive regulator of ER activity. Here, we demonstrate that depletion of KDM3A by RNAi abrogates the recruitment of the ER to cis-regulatory elements within target gene promoters, thereby inhibiting estrogen-induced gene expression changes. Global gene expression analysis of KDM3A-depleted cells identified gene clusters associated with cell growth. Consistent with this, we show that knockdown of KDM3A reduces ER-positive cell proliferation and demonstrate that KDM3A is required for growth in a model of endocrine therapy-resistant disease. Crucially, we show that KDM3A catalytic activity is required for both ER-target gene expression and cell growth, demonstrating that developing compounds which target demethylase enzymatic activity may be efficacious in treating both ER-positive and endocrine therapy-resistant disease.
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spelling pubmed-42881882015-02-19 The histone demethylase enzyme KDM3A is a key estrogen receptor regulator in breast cancer Wade, Mark A. Jones, Dominic Wilson, Laura Stockley, Jacqueline Coffey, Kelly Robson, Craig N. Gaughan, Luke Nucleic Acids Res Gene regulation, Chromatin and Epigenetics Endocrine therapy has successfully been used to treat estrogen receptor (ER)-positive breast cancer, but this invariably fails with cancers becoming refractory to treatment. Emerging evidence has suggested that fluctuations in ER co-regulatory protein expression may facilitate resistance to therapy and be involved in breast cancer progression. To date, a small number of enzymes that control methylation status of histones have been identified as co-regulators of ER signalling. We have identified the histone H3 lysine 9 mono- and di-methyl demethylase enzyme KDM3A as a positive regulator of ER activity. Here, we demonstrate that depletion of KDM3A by RNAi abrogates the recruitment of the ER to cis-regulatory elements within target gene promoters, thereby inhibiting estrogen-induced gene expression changes. Global gene expression analysis of KDM3A-depleted cells identified gene clusters associated with cell growth. Consistent with this, we show that knockdown of KDM3A reduces ER-positive cell proliferation and demonstrate that KDM3A is required for growth in a model of endocrine therapy-resistant disease. Crucially, we show that KDM3A catalytic activity is required for both ER-target gene expression and cell growth, demonstrating that developing compounds which target demethylase enzymatic activity may be efficacious in treating both ER-positive and endocrine therapy-resistant disease. Oxford University Press 2015-01-09 2014-12-08 /pmc/articles/PMC4288188/ /pubmed/25488809 http://dx.doi.org/10.1093/nar/gku1298 Text en © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research. http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Gene regulation, Chromatin and Epigenetics
Wade, Mark A.
Jones, Dominic
Wilson, Laura
Stockley, Jacqueline
Coffey, Kelly
Robson, Craig N.
Gaughan, Luke
The histone demethylase enzyme KDM3A is a key estrogen receptor regulator in breast cancer
title The histone demethylase enzyme KDM3A is a key estrogen receptor regulator in breast cancer
title_full The histone demethylase enzyme KDM3A is a key estrogen receptor regulator in breast cancer
title_fullStr The histone demethylase enzyme KDM3A is a key estrogen receptor regulator in breast cancer
title_full_unstemmed The histone demethylase enzyme KDM3A is a key estrogen receptor regulator in breast cancer
title_short The histone demethylase enzyme KDM3A is a key estrogen receptor regulator in breast cancer
title_sort histone demethylase enzyme kdm3a is a key estrogen receptor regulator in breast cancer
topic Gene regulation, Chromatin and Epigenetics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4288188/
https://www.ncbi.nlm.nih.gov/pubmed/25488809
http://dx.doi.org/10.1093/nar/gku1298
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