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Open AccessArticle

The Histone Demethylase Enzymes KDM3A and KDM4B Co-Operatively Regulate Chromatin Transactions of the Estrogen Receptor in Breast Cancer

1
Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
2
Biomedical Sciences, Faculty of Health Sciences, University of Hull, Hull HU6 7RX, UK
*
Author to whom correspondence should be addressed.
Cancers 2019, 11(8), 1122; https://doi.org/10.3390/cancers11081122
Received: 24 June 2019 / Revised: 29 July 2019 / Accepted: 3 August 2019 / Published: 6 August 2019
(This article belongs to the Special Issue Estrogen Receptor (ER) Signalling Pathway in Cancers)
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Abstract

Many estrogen receptor (ER)-positive breast cancers develop resistance to endocrine therapy but retain canonical receptor signalling in the presence of selective ER antagonists. Numerous co-regulatory proteins, including enzymes that modulate the chromatin environment, control the transcriptional activity of the ER. Targeting ER co-regulators has therefore been proposed as a novel therapeutic approach. By assessing DNA-binding dynamics in ER-positive breast cancer cells, we have identified that the histone H3 lysine 9 demethylase enzymes, KDM3A and KDM4B, co-operate to regulate ER activity via an auto-regulatory loop that facilitates the recruitment of each co-activating enzyme to chromatin. We also provide evidence that suggests that KDM3A primes chromatin for deposition of the ER pioneer factor FOXA1 and recruitment of the ER-transcriptional complex, all prior to ER recruitment, therefore establishing an important mechanism of chromatin regulation involving histone demethylases and pioneer factors, which controls ER functionality. Importantly, we show via global gene-expression analysis that a KDM3A/KDM4B/FOXA1 co-regulated gene signature is enriched for pro-proliferative and ER-target gene sets, suggesting that abrogation of this network could be an efficacious therapeutic strategy. Finally, we show that depletion of both KDM3A and KDM4B has a greater inhibitory effect on ER activity and cell growth than knockdown of each individual enzyme, suggesting that targeting both enzymes represents a potentially efficacious therapeutic option for ER-driven breast cancer. View Full-Text
Keywords: epigenetics; histone demethylation; estrogen receptor; breast cancer epigenetics; histone demethylation; estrogen receptor; breast cancer
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Jones, D.; Wilson, L.; Thomas, H.; Gaughan, L.; Wade, M.A. The Histone Demethylase Enzymes KDM3A and KDM4B Co-Operatively Regulate Chromatin Transactions of the Estrogen Receptor in Breast Cancer. Cancers 2019, 11, 1122.

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