Histone Deacetylase Inhibitors Stimulate Histone H3 Lysine 4 Methylation in Part Via Transcriptional Repression of Histone H3 Lysine 4 Demethylases

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 ( -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.

Loss of H3K4 methylation destabilizes gene expression patterns and physiological functions in adult murine cardiomyocytes

“…Such permanent alterations are thought to be due to epigenetic changes at gene-specific promoter regions. Histone deacetylase inhibitors are now used as anticancer or anticonvulsive drugs but can lead to unintended alterations in the methylation of histones in a variety of tissues (33)(34)(35). Furthermore, the metabolic memory hypothesis presupposes that once a pattern of histone methylation is reset by stress, that pattern is maintained or replicated.…”

Whole-genome sequencing reveals oncogenic mutations in mycosis fungoides

“…Our results are interesting given the successful treatment of some MF patients with histone deacetylase inhibitors (HDACi), which have been shown to stimulate methylation of H3K4. 50 We hypothesize mutations in the genes that regulate H3K4 methylation lead to reduced methylation, closed chromatin, and reduced transcription of tumor suppressors, which can be reversed with HDACi. These will be important areas in the future on which to focus research efforts.…”

“…Of the genes mutated, 3 of them have a specific role in the methylation of H3K4, which is associated with open chromatin and active transcription. 50 MLL2 is a tumor suppressor and histone methyltransferase that helps to methylate H3K4. 51 MLL2 mutations were identified in B-cell lymphomas, and our novel mutation (C8788T, P2930S) is in a similar region as several previously identified.…”

Echinomycin protects mice against relapsed acute myeloid leukemia without adverse effect on hematopoietic stem cells

“…18 The Mll PTD/WT :Flt3 ITD/WT AML mouse uniformly relapses with resistant disease following treatment with a DNA hypomethylating agent and/or a histone deacetylase (HDAC) inhibitor. 27 Here we report that echinomycin administered as intraperitoneal injection for a total of 4 doses), followed by 50 mg/kg of (S)-(1)-N-hydroxy-4-(3-methyl-2-phenyl-butyrylamino)-benzamide (an HDAC inhibitor 28 ) given orally every other day for 3 doses. This regimen has been shown to be temporarily effective in the Mll PTD/WT :Flt3 ITD/WT AML murine model and therefore suitable to test our hypothesis.…”