A KDM5 Inhibitor Increases Global H3K4 Trimethylation Occupancy and Enhances the Biological Efficacy of 5-Aza-2′-Deoxycytidine

Abstract

The H3K4 demethylase <i>KDM5B</i> is amplified and overexpressed in luminal breast cancer, suggesting it might constitute a potential cancer therapy target. Here, we characterize, in breast cancer cells, the molecular effects of a recently developed small-molecule inhibitor of the KDM5 family of proteins (KDM5i), either alone or in combination with the DNA-demethylating agent 5-aza-2'-deoxycytidine (DAC). KDM5i treatment alone increased expression of a small number of genes, whereas combined treatment with DAC enhanced the effects of the latter for increasing expression of hundreds of DAC-responsive genes. ChIP-seq studies revealed that KDM5i resulted in the broadening of existing H3K4me3 peaks. Furthermore, cells treated with the drug combination exhibited increased promoter and gene body H3K4me3 occupancy at DAC-responsive genes compared with DAC alone. Importantly, treatment with either DAC or DAC+KDM5i induced a dramatic increase in H3K27ac at enhancers with an associated significant increase in target gene expression, suggesting a previously unappreciated effect of DAC on transcriptional regulation. KDM5i synergized with DAC to reduce the viability of luminal breast cancer cells in <i>in vitro</i> assays. Our study provides the first look into the molecular effects of a novel KDM5i compound and suggests that combinatorial inhibition along with DAC represents a new area to explore in translational epigenetics.<b>Significance:</b> This study offers a first look into the molecular effects of a novel KDM5 inhibitory compound, suggesting how its use in combination with DNA methylation inhibitors presents new opportunities to explore in translational cancer epigenetics. <i>Cancer Res; 78(5); 1127-39. ©2017 AACR</i>.