Histone Deacetylase Inhibitor Depsipeptide Activates Silenced Genes through Decreasing both CpG and H3K9 Methylation on the Promoter

Abstract

Histone deacetylase inhibitor (HDACi) has been shown to demethylate the 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, a 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 trimethylated H3K9 around these genes' promoter. Furthermore, both loading of heterochromatin-associated protein 1 (HP1␣ and HP1␤) to methylated H3K9 and binding of DNMT1 to these genes' promoter were significantly reduced in depsipeptide-treated cells. Similar DNA demethylation was induced by another HDAC inhibitor, apicidin, but not by trichostatin A. Our data describe a novel mechanism of HDACi-mediated DNA demethylation via suppression of histone methyltransferases and reduced recruitment of HP1 and DNMT1 to the genes' promoter.

Repression of IP-10 by Interactions between Histone Deacetylation and Hypermethylation in Idiopathic Pulmonary Fibrosis

“…This is consistent with previous findings that the HDAC inhibitor LBH589 releases SUV39H1 from silenced estrogen receptor alpha (ER) gene promoter, which is associated with a decrease in H3K9 methylation and impaired binding of HP1 at the promoter, resulting in the restoration of ER gene expression (49) and that the HDAC inhibitor depsipeptide activates silenced genes by suppressing the expression of G9a and SUV39H1 and reducing H3K9me2 and H3K9me3 at these gene promoters and HP1 loading to H3K9me3 (44). However, whether HDAC inhibitors restore IP-10 gene expression by suppressing the expression of G9a and SUV39H1 in F-IPF cells requires further investigation.…”

“…HDAC-mediated histone deacetylation is necessary for Dnmt1 to carry out its methylation function (10), and the presence of deacetylated histones allows SUV39H1-mediated H3K9 trimethylation to take place (4,19). Indeed, HDAC inhibitors have been shown to reduce Dnmt1 binding to silenced gene promoters and reduce DNA methylation, resulting in the restoration of silenced gene expression (44,49). Thus, cross talk between histone deacetylation, methylation, and DNA methylation is believed to be necessary for the generation of a stable and long-term epigenetically silenced state in cancer.…”

Valproate and Amitriptyline Exert Common and Divergent Influences on Global and Gene Promoter-Specific Chromatin Modifications in Rat Primary Astrocytes

“…Our data show that VPA exposure caused a slight but specific reduction in the levels of dimethyl-H3K9, leaving dimethyl-H3K27 unchanged. In line with our results, HDAC-I desipeptide decreases the level of H3K9 methylation and induces DNA demethylation by reducing G9A and SUV39H1 activity and DNMT-1 binding, respectively (Wu et al, 2008b). In contrast to VPA, AMI did not change dimethyl-H3K9 levels.…”

Histone deacetylase inhibitors induce CXCR4 mRNA but antagonize CXCR4 migration

“…19 Romidepsin is effective in inducing demethylation in the human lung cancer cell lines H719 and H23, human pancreatic cancer cell line PANC1 and human colon cancer cell line HT29 but not in human colon cancer cell lines HCT116 and SW480. 38 In cells lines SF295 and H460, romidepsin induced CXCR4 but no induction was registered in SW620 and MCF7 cells. It is interesting to note that the two cell lines not further induced in CXCR4 mRNA expression by HDIs, MCF7 and HDI treatment reduced cell migration in response to CXCL12.…”