Browse by author
Lookup NU author(s): Dr Dominic Jones, Laura WilsonORCiD, Huw ThomasORCiD, Dr Luke GaughanORCiD, Dr Mark Wade
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2019 by the authors. Licensee MDPI, Basel, Switzerland.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.
Author(s): Jones D, Wilson L, Thomas H, Gaughan L, Wade MA
Publication type: Article
Publication status: Published
Journal: Cancers
Year: 2019
Volume: 11
Issue: 8
Online publication date: 06/08/2019
Acceptance date: 03/08/2019
Date deposited: 02/09/2019
ISSN (electronic): 2072-6694
Publisher: MDPI AG
URL: https://doi.org/10.3390/cancers11081122
DOI: 10.3390/cancers11081122
Altmetrics provided by Altmetric
