The histone demethylase enzymes KDM3A and KDM4B co-operatively regulate chromatin transactions of the estrogen receptor in breast cancer

Jones, Dominic; Wilson, Laura; Thomas, Huw; Gaughan, Luke; Wade, Mark A.

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.

Citation

Jones, D., Wilson, L., Thomas, H., Gaughan, L., & Wade, M. A. (2019). The histone demethylase enzymes KDM3A and KDM4B co-operatively regulate chromatin transactions of the estrogen receptor in breast cancer. Cancers, 11(8), Article 1122. https://doi.org/10.3390/cancers11081122

• Journal Article Type: Article
• Acceptance Date: Aug 3, 2019
• Online Publication Date: Aug 6, 2019
• Publication Date: Aug 1, 2019
• Deposit Date: Aug 7, 2019
• Publicly Available Date: Aug 7, 2019
• Journal: Cancers
• Electronic ISSN: 2072-6694
• Publisher: MDPI
• Peer Reviewed: Peer Reviewed
• Volume: 11
• Issue: 8
• Article Number: 1122
• DOI: https://doi.org/10.3390/cancers11081122
• Keywords: Epigenetics; Histone demethylation; Estrogen receptor; Breast cancer; Cancer research
• Public URL: https://hull-repository.worktribe.com/output/2321408
• Publisher URL: https://www.mdpi.com/2072-6694/11/8/1122
• Additional Information: © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
• Contract Date: Aug 7, 2019