title: Glutathione-S-transferase pi 1(GSTP1) gene silencing in prostate cancer cells is reversed by the histone deacetylase inhibitor depsipeptide.
abstract: Gene silencing by epigenetic mechanisms is frequent in prostate cancer (PCA). The link between DNA hypermethylation and histone modifications is not completely understood. We chose the GSTP1 gene which is silenced by hypermethylation to analyze the effect of the histone deacetylase inhibitor depsipeptide on DNA methylation and histone modifications at the GSTP1 promoter site. Prostate cell lines (PC-3, LNCaP, and BPH-1) were treated with depsipeptide; apoptosis (FACS analysis), GSTP1 mRNA levels (quantitative real-time PCR), DNA hypermethylation (methylation-specific PCR), and histone modifications (chromatin immunoprecipitation) were studied. Depsipeptide induced apoptosis in PCA cells, but not a cell cycle arrest. Depispeptide reversed DNA hypermethylation and repressive histone modifications (reduction of H3K9me2/3 and H3K27me2/3; increase of H3K18Ac), thereby inducing GSTP1 mRNA re-expression. Successful therapy requires both, DNA demethylation and activating histone modifications, to induce complete gene expression of epigenetically silenced genes and depsipeptide fulfils both criteria.
authors.affiliation: Department of Pathology, University Hospital Bonn, Bonn, Germany. verahauptstock@gmx.de
authors.forename: Vera
authors.initials: V
authors.lastname: Hauptstock
authors.forename: Sapuna
authors.initials: S
authors.lastname: Kuriakose
authors.forename: Doris
authors.initials: D
authors.lastname: Schmidt
authors.forename: Robert
authors.initials: R
authors.lastname: Düster
authors.forename: Stefan C
authors.initials: SC
authors.lastname: Müller
authors.forename: Alexander
authors.initials: A
authors.lastname: von Ruecker
authors.forename: Jörg
authors.initials: J
authors.lastname: Ellinger
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D019175:DNA Methylation / Q000187:drug effects*; D047630:Depsipeptides / Q000494:pharmacology*; D020868:Gene Silencing / Q000187:drug effects*; D051549:Glutathione S-Transferase pi / Q000096:biosynthesis* / Q000235:genetics; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000235:genetics*
chemical_list: D047630:Depsipeptides; D056572:Histone Deacetylase Inhibitors; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi