Novel Histone Demethylase Inhibitors Synergistically Enhance the Effects of a DNA Hypomethylating Agent in Breast Cancer Cells

Epigenetics;KDM5;Breast Cancer;Human Genetics and Molecular Biology

Leadem, Benjamin RobertCasero, Robert A. (Bob) ;

Johns Hopkins University

关键词: Epigenetics;    KDM5;    Breast Cancer;    Human Genetics and Molecular Biology;   

Others  :  https://jscholarship.library.jhu.edu/bitstream/handle/1774.2/37853/LEADEM-DISSERTATION-2015.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: JOHNS HOPKINS DSpace Repository

【 摘 要 】

DNA methylation and histone methylation function together in the epigenetic regulation of gene expression, but these processes can be altered in cancer.Recently, the H3K4 demethylase, KDM5B, was shown to be amplified and overexpressed in luminal breast cancer, making it an ideal target for chemotherapeutic intervention.In this study, we characterized the phenotypic and molecular effects of a novel group of KDM5 inhibitors, either alone or in combination with the DNA demethylating agent 5-Aza-2’-deoxycytidine (DAC), in luminal breast cancer cells.We found that KDM5 inhibitors and DAC synergistically inhibit cell proliferation and induce apoptosis relative to each drug alone.Additionally, microarray analysis indicated that combination treatment with KDM5 inhibitors and DAC resulted in the significant upregulation of hundreds of genes relative to DAC alone.Among these targets was an enrichment for genes in immunomodulatory pathways which are upregulated after exposure to the DNA demethylating agent 5-azacytidine.We then analyzed whole genome DNA methylation levels using the Infinium 450k microarray and, when compared to DAC treatment alone, found no additional loss of DNA methylation in the combination treatment.Instead, upregulaton of target genes appears to be mediated, at least in part, by a specific increase in H3K4 trimethylation levels at the at target promoters following exposure to the KDM5 inhibitors. Our results indicate that target genes are regulated by both DNA methylation and histone methylation in breast cancer cells.Upregulation of these genes via combined KDM5 inhibitor and DAC treatment leads to the synergistic inhibition of proliferation and may represent an exciting new application for epigenetic therapy in the treatment of breast cancer.