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

Wade, M. A., Jones, D., Wilson, L., Stockley, J., Coffey, K., Robson, C. N. and Gaughan, L. (2015) The histone demethylase enzyme KDM3A is a key estrogen receptor regulator in breast cancer. Nucleic Acids Research, 43(1), pp. 196-207. (doi: 10.1093/nar/gku1298) (PMID:25488809) (PMCID:PMC4288188)

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 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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Stockley, Dr Jacqueline
• Authors: Wade, M. A., Jones, D., Wilson, L., Stockley, J., Coffey, K., Robson, C. N., and Gaughan, L.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Nucleic Acids Research
• Publisher: Oxford University Press
• ISSN: 0305-1048
• ISSN (Online): 1362-4962
• Copyright Holders: Copyright © 2014 The Authors
• First Published: First published in Nucleic Acids Research 43(1):196-207
• Publisher Policy: Reproduced under a Creative Commons License