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.
Highlights
Estrogen receptor (ER) signalling is important for breast cell homeostasis and transformation and remains the primary target for therapeutic intervention in breast cancer (BC)
We show that KDM3A and KDM4B interact in BC cells and are involved in an auto-regulatory loop whereby KDM4B regulates the expression of KDM3A, and KDM3A facilitates the recruitment of KDM4B to ER cis-regulatory elements
We have previously shown that both KDM3A and KDM4B are required for ER recruitment to cis-regulatory elements of ER
Summary
Estrogen receptor (ER) signalling is important for breast cell homeostasis and transformation and remains the primary target for therapeutic intervention in breast cancer (BC). ER-mediated transactivation is under tight control by a myriad of co-factors regulating the transcriptional competency of the receptor at numerous levels [1,2]. Several lines of evidence have indicated that chromatin deposition of pioneer factors FOXA1 and GATA3 at ER-target loci is critical for enabling appropriate. Aberrant activity of ER co-regulators drives the progression of BC [1,2,7,8,9]. In light of the fact that therapeutically targeting the ER directly in BC routinely fails, developing treatments that target critical ER co-regulators may provide an effective second-line treatment for endocrine
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