Department of Oncology, the Sidney Kimmel Comprehensive Cancer Research Center at Johns Hopkins University, Baltimore, Maryland.
Molecular Oncology, Genentech Inc., South San Francisco, California.
Cancer Res. 2018 Mar 1;78(5):1127-1139. doi: 10.1158/0008-5472.CAN-17-1453. Epub 2017 Dec 27.
The H3K4 demethylase 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 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. 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. .
H3K4 去甲基化酶在腔乳腺癌中扩增和过表达，提示其可能构成潜在的癌症治疗靶点。在这里，我们在乳腺癌细胞中描述了一种新开发的 KDM5 家族蛋白小分子抑制剂（KDM5i）的分子作用，单独使用或与 DNA 去甲基化剂 5-aza-2'-脱氧胞苷（DAC）联合使用。KDM5i 单独处理仅增加少数基因的表达，而与 DAC 联合处理增强了后者增加数百个 DAC 反应基因表达的效果。ChIP-seq 研究表明，KDM5i 导致现有的 H3K4me3 峰变宽。此外，与单独使用 DAC 相比，用药物组合处理的细胞在 DAC 反应基因上显示出增强的启动子和基因体 H3K4me3 占有率。重要的是，用 DAC 或 DAC+KDM5i 处理均可在增强子上诱导 H3K27ac 的急剧增加，伴随着靶基因表达的显著增加，表明 DAC 对转录调控有以前未被认识到的影响。在测定中，KDM5i 与 DAC 协同降低腔乳腺癌细胞的活力。我们的研究首次观察到一种新型 KDM5i 化合物的分子作用，并表明与 DAC 联合抑制代表了转化表观遗传学中一个新的探索领域。
