HDAC Inhibitor Depsipeptide Activates Silenced Genes Through Decreasing Both CpG And H3K9 Methylation On The Promoter

Histone deacetylase inhibitor (HDACi) has been shown to demethylate mammalian genome, which further strengthens the concept that DNA methylation and histone modifications interact in regulation of gene expression. Here, we report that an HDAC inhibitor, depsipeptide, exhibited significant demethylating activity on the promoters of several genes including p16, SALL3 and GATA4 in human lung cancer cell lines H719 and H23, colon cancer cell line HT-29 and pancreatic cancer cell line PANC1. Although expression of DNA methyltransferase 1 (DNMT1) was not affected by depsipeptide, decrease in binding of DNMT1 to the promoter of these genes played a dominant role in depsipeptide-induced demethylation and reactivation. Depsipeptide also suppressed expression of histone methyltransferases G9A and SUV39H1 which in turn resulted in a decrease of di- and tri-methylated H3K9 around these genes'promoter. Furthermore, both loading of heterochromatin-associated protein1 (HP1αand HP1β) to methylated H3K9 and binding of DNMT1 to these genes'promoter were significantly reduced in desipeptide treated cells. Similar DNA demethylation was induced by another HDAC inhibitor apicidin A, but not by TSA. Our data describes a novel mechanism of HDACi-mediated DNA demethylation via suppression of histone methyltransferases and reduced recruitment of HP1 and DNMT1 to the gene's promoter.