GSE111293
Combination Treatment of Acute Myeloid Leukemia Cells with DNMT and HDAC Inhibitors: Predominant Synergistic Gene Downregulation Associated with Gene Body Demethylation
DNA-hypomethylating agents approved for older AML patients, are clinically tested in combination with histone deacetylase inhibitors (HDACi).The mechanism of action of these drugs is still under debate. In colon cancer cells, 5-aza-2''deoxycytidine (DAC) can downregulate oncogenes and metabolic genes by reversing gene body DNA methylation, thus implicating gene body methylation as a novel drug target. We asked whether DAC-induced gene body demethylation in AML cells is also associated with gene repression, and whether the latter is enhanced by HDACi. Transcriptome analyses revealed that a combined treatment with DAC and HDACi panobinostat or valproic acid effected significantly more transcripts than the sum of the genes regulated by either treatment alone, demonstrating a quantitative synergistic effect on genome-wide expression in U937 cells. This effect was particularly striking for downregulated genes. Integrative analysis of the methylome and transcriptome showed that a massive downregulation of genes, including oncogenes (e.g.c-MYC) and epigenetic modifiers (e.g. KDM2B and SUV39H1) often overexpressed in cancer, was associated predominantly with gene body DNA demethylation, and changes in acH3K9/27. These findings have implications for the mechanism of action of combined epigenetic treatment, and for a better understanding of responses in trials where this approach is clinically tested. Overall design: Examination of H3K9 acetylation and H3K27 acetylation in U937 cells after decitabine +- panobinostat/entinostat treatment