title: 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 (HP1alpha and HP1beta) 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Peking University Health Science Center, 38 Xueyuan Road, Beijing 100083, China.
authors.forename: Li-Peng
authors.initials: LP
authors.lastname: Wu
authors.forename: Xi
authors.initials: X
authors.lastname: Wang
authors.forename: Lian
authors.initials: L
authors.lastname: Li
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhao
authors.forename: Shaoli
authors.initials: S
authors.lastname: Lu
authors.forename: Yu
authors.initials: Y
authors.lastname: Yu
authors.forename: Wen
authors.initials: W
authors.lastname: Zhou
authors.forename: Xiangyu
authors.initials: X
authors.lastname: Liu
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.forename: Zhixin
authors.initials: Z
authors.lastname: Zheng
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.forename: Jingnan
authors.initials: J
authors.lastname: Feng
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.forename: Haiying
authors.initials: H
authors.lastname: Wang
authors.forename: Wei-Guo
authors.initials: WG
authors.lastname: Zhu
mesh_terms: D001483:Base Sequence; D045744:Cell Line, Tumor; D000090266:Chromobox Protein Homolog 5; D018899:CpG Islands; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects; D000090205:DNA Methyltransferase 3A; D017931:DNA Primers / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D047630:Depsipeptides / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D020868:Gene Silencing; D019942:Genes, p16; D006649:Histocompatibility Antigens / Q000235:genetics; D056572:Histone Deacetylase Inhibitors; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors / Q000235:genetics; D006657:Histones / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008780:Methyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics
chemical_list: C000715593:CBX1 protein, human; C000715594:CBX5 protein, human; D017931:DNA Primers; D004273:DNA, Neoplasm; C000717967:DNMT3A protein, human; D047630:Depsipeptides; D004791:Enzyme Inhibitors; D006649:Histocompatibility Antigens; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D012097:Repressor Proteins; D000090266:Chromobox Protein Homolog 5; C407843:SUV39H1 protein, human; D008780:Methyltransferases; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; C000619380:DNMT1 protein, human; C445405:EHMT2 protein, human; D011495:Histone-Lysine N-Methyltransferase