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KDM4B is a master regulator of the estrogen receptor signalling cascade

Gaughan, Luke; Stockley, Jacqueline; Coffey, Kelly; O’Neill, Daniel; Jones, Dominic L.; Wade, Mark; Wright, Jamie; Moore, Madeleine; Tse, Sandy; Rogerson, Lynsey; Robson, Craig N.

Authors

Luke Gaughan

Jacqueline Stockley

Kelly Coffey

Daniel O’Neill

Dominic L. Jones

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Dr Mark Wade M.Wade@hull.ac.uk
Senior Lecturer in Molecular Genetics

Jamie Wright

Madeleine Moore

Sandy Tse

Lynsey Rogerson

Craig N. Robson



Abstract

The importance of the estrogen receptor (ER) in breast cancer (BCa) development makes it a prominent target for therapy. Current treatments, however, have limited effectiveness, and hence the definition of new therapeutic targets is vital. The ER is a member of the nuclear hormone receptor superfamily of transcription factors that requires co-regulator proteins for complete regulation. Emerging evidence has implicated a small number of histone methyltransferase (HMT) and histone demethylase (HDM) enzymes as regulators of ER signalling, including the histone H3 lysine 9 tri-/di-methyl HDM enzyme KDM4B. Two recent independent reports have demonstrated that KDM4B is required for ER-mediated transcription and depletion of the enzyme attenuates BCa growth in vitro and in vivo. Here we show that KDM4B has an overarching regulatory role in the ER signalling cascade by controlling expression of the ER and FOXA1 genes, two critical components for maintenance of the estrogen-dependent phenotype. KDM4B interacts with the transcription factor GATA-3 in BCa cell lines and directly co-activates GATA-3 activity in reporter-based experiments. Moreover, we reveal that KDM4B recruitment and demethylation of repressive H3K9me3 marks within upstream regulatory regions of the ER gene permits binding of GATA-3 to drive receptor expression. Ultimately, our findings confirm the importance of KDM4B within the ER signalling cascade and as a potential therapeutic target for BCa treatment.

Citation

Gaughan, L., Stockley, J., Coffey, K., O’Neill, D., Jones, D. L., Wade, M., …Robson, C. N. (2013). KDM4B is a master regulator of the estrogen receptor signalling cascade. Nucleic Acids Research, 41(14), 6892-6904. https://doi.org/10.1093/nar/gkt469

Journal Article Type Article
Acceptance Date May 3, 2013
Online Publication Date May 30, 2013
Publication Date Aug 1, 2013
Deposit Date Feb 4, 2019
Publicly Available Date Mar 28, 2024
Journal Nucleic Acids Research
Print ISSN 0305-1048
Electronic ISSN 1362-4962
Publisher Oxford University Press
Peer Reviewed Peer Reviewed
Volume 41
Issue 14
Pages 6892-6904
DOI https://doi.org/10.1093/nar/gkt469
Public URL https://hull-repository.worktribe.com/output/1271185
Publisher URL https://academic.oup.com/nar/article/41/14/6892/1080007

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Publisher Licence URL
http://creativecommons.org/licenses/by/3.0

Copyright Statement
ßThe Author(s) 2013. Published by Oxford University Press.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/), whichpermits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.Downloaded from https://academic.oup.com/nar/article-abstract/41/14/6892/1080007 by University of Hull user on 04 February 2019





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