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

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.

Citation

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

• Journal Article Type: Article
• Acceptance Date: Nov 29, 2014
• Online Publication Date: Dec 8, 2014
• Publication Date: Jan 9, 2015
• Deposit Date: Feb 4, 2019
• Publicly Available Date: Mar 12, 2021
• Journal: Nucleic Acids Research
• Print ISSN: 0305-1048
• Electronic ISSN: 1362-4962
• Publisher: Oxford University Press
• Peer Reviewed: Peer Reviewed
• Volume: 43
• Issue: 1
• Pages: 196-207
• DOI: https://doi.org/10.1093/nar/gku1298
• Public URL: https://hull-repository.worktribe.com/output/1271236
• Publisher URL: https://academic.oup.com/nar/article/43/1/196/1007966