Document Detail

Histone deacetylase inhibitors stimulate histone H3 lysine 4 methylation in part via transcriptional repression of histone H3 lysine 4 demethylases.
MedLine Citation:
PMID:  20959362     Owner:  NLM     Status:  MEDLINE    
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)-aminomethyl]-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.
Po-Hsien Huang; Chun-Han Chen; Chih-Chien Chou; Aaron M Sargeant; Samuel K Kulp; Che-Ming Teng; John C Byrd; Ching-Shih Chen
Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2010-10-19
Journal Detail:
Title:  Molecular pharmacology     Volume:  79     ISSN:  1521-0111     ISO Abbreviation:  Mol. Pharmacol.     Publication Date:  2011 Jan 
Date Detail:
Created Date:  2010-12-15     Completed Date:  2011-01-13     Revised Date:  2013-07-03    
Medline Journal Info:
Nlm Unique ID:  0035623     Medline TA:  Mol Pharmacol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  197-206     Citation Subset:  IM    
Division of Medicinal Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.
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MeSH Terms
Base Sequence
Binding Sites / genetics
Cell Line, Tumor
DNA Methylation / drug effects
Histone Deacetylase Inhibitors / pharmacology*
Mice, Inbred C57BL
Mice, Transgenic
Molecular Sequence Data
Oxidoreductases, N-Demethylating / antagonists & inhibitors*,  biosynthesis*,  genetics
Transcription, Genetic / drug effects*,  genetics
Grant Support
Reg. No./Substance:
0/Histone Deacetylase Inhibitors; EC 1.5.-/Oxidoreductases, N-Demethylating; EC 1.5.-/kdm1b protein, mouse

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