Histone deacetylase inhibitors stimulate histone H3 lysine 4 methylation in part via transcriptional repression of histone H3 lysine 4 demethylases
Journal
Molecular Pharmacology
Journal Volume
79
Journal Issue
1
Pages
197-206
Date Issued
2011
Author(s)
CHE-MING TENG
Abstract
This study investigates the mechanism by which histone deacetylase (HDAC) inhibitors up-regulate histone H3 lysine 4 (H3K4) methylation. Exposure of LNCaP prostate cancer cells and the prostate tissue of transgenic adenocarcinoma of the mouse prostate mice to the pan- and class I HDAC inhibitors (S)-(+)-N-hydroxy-4-(3-methyl-2-phenyl-butyrylamino)-benzamide (AR42), N-(2-aminophenyl)-4-[N-(pyridine-3-yl-methoxycarbonyl)-amino-methyl]-benzamide (MS-275), and vorinostat led to differential increases in H3K4 methylation. Chromatin immunoprecipitation shows that this accumulation of methylated H3K4 occurred in conjunction with decreases in the amount of the H3K4 demethylase RBP2 at the promoter of genes associated with tumor suppression and differentiation, including KLF4 and E-cadherin. This finding, together with the HDAC inhibitor-induced up-regulation of KLF4 and E-cadherin, suggests that HDAC inhibitors could activate the expression of these genes through changes in histone methylation status. Evidence indicates that this up-regulation of H3K4 methylation was attributable to the suppressive effect of these HDAC inhibitors on the expression of RBP2 and other JARID1 family histone demethylases, including PLU-1, SMCX, and LSD1, via the down-regulation of Sp1 expression. Moreover, shRNA-mediated silencing of the class I HDAC isozymes 1, 2, 3, and 8, but not that of the class II isozyme HDAC6, mimicked the drug effects on H3K4 methylation and H3K4 demethylases, which could be reversed by ectopic Sp1 expression. These data suggest a cross-talk mechanism between HDACs and H3K4 demethylases via Sp1-mediated transcriptional regulation, which underlies the complexity of the functional role of HDACs in the regulation of histone modifications. Copyright ? 2011 The American Society for Pharmacology and Experimental Therapeutics.
SDGs
Other Subjects
ar 42; entinostat; histone deacetylase 1; histone deacetylase 2; histone deacetylase 3; histone deacetylase 6; histone deacetylase 8; histone deacetylase inhibitor; histone demethylase; histone h3 lysine 4 demethylase; jumonji AT rich interactive domain 1C; jumonji T rich interactive domain 1B; kruppel like factor 4; lysine specific demethylase; n hydroxy 4 (3 methyl 2 phenylbutyrylamino)benzamide; retinoblastoma binding protein 2; short hairpin RNA; transcription factor Sp1; unclassified drug; uvomorulin; vorinostat; animal experiment; article; cancer cell; cancer inhibition; cell viability; down regulation; drug effect; gene activation; gene expression; gene repression; gene silencing; genetic transcription; histone methylation; mouse; nonhuman; nucleotide sequence; priority journal; promoter region; prostate cancer; upregulation; Animals; Base Sequence; Binding Sites; Cell Line, Tumor; DNA Methylation; Histone Deacetylase Inhibitors; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Molecular Sequence Data; Oxidoreductases, N-Demethylating; Transcription, Genetic
Type
journal article