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

Lookup NU author(s): Dr Mark Wade, Dominic Jones, Laura WilsonORCiD, Dr Jacqueline Stockley, Dr Kelly CoffeyORCiD, Professor Craig RobsonORCiD, Dr Luke GaughanORCiD

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

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 knock-down 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.

Publication metadata

Author(s): Wade MA, Jones D, Wilson L, Stockley J, Coffey K, Robson CN, Gaughan L

Publication type: Article

Publication status: Published

Journal: Nucleic Acids Research

Year: 2015

Volume: 43

Issue: 1

Pages: 196-207

Print publication date: 01/01/2015

Online publication date: 08/12/2014

Acceptance date: 29/11/2014

Date deposited: 14/12/2015

ISSN (print): 0305-1048

ISSN (electronic): 1362-4962

Publisher: Oxford University Press

URL: http://dx.doi.org/10.1093/nar/gku1298

DOI: 10.1093/nar/gku1298

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