Histone Deacetylase Inhibitors Stimulate Histone H3 Lysine 4 Methylation in Part Via Transcriptional Repression of Histone H3 Lysine 4 Demethylases
Histone Deacetylase Inhibitors Stimulate Histone H3 Lysine 4 Methylation in Part Via Transcriptional Repression of Histone H3 Lysine 4 Demethylases
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DOI：
10.1124/mol.110.067702
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发表时间：
2011-01-01
影响因子：
3.6
通讯作者：
Chen, Ching-Shih
中科院分区：
文献类型：
--
作者：
Huang, Po-Hsien;Chen, Chun-Han;Chen, Ching-Shih
本研究探讨了组蛋白去乙酰化酶（HDAC）抑制剂上调组蛋白H3赖氨酸4（H3 K4）甲基化的机制。将LNCaP前列腺癌细胞和小鼠前列腺小鼠的转基因腺癌的前列腺组织暴露于泛HDAC抑制剂和I类HDAC抑制剂（S）-（+）-N-羟基-4-（3-甲基-2-苯基-丁酰氨基）-苯甲酰胺（AR 42）、N-（2-氨基苯基）-4-[N-（吡啶-3-基-甲氧羰基）-氨基甲基]-苯甲酰胺（MS-275）和伏立诺他导致H3 K4甲基化的差异性增加。染色质免疫沉淀显示，甲基化H3 K4的这种积累与肿瘤抑制和分化相关基因（包括KLF 4和E-钙粘蛋白）启动子处H3 K4脱甲基酶RBP 2的量减少有关。这一发现，以及HDAC抑制剂诱导的KLF 4和E-cadherin的上调，表明HDAC抑制剂可以通过改变组蛋白甲基化状态来激活这些基因的表达。有证据表明，H3 K4甲基化的这种上调归因于这些HDAC抑制剂通过下调Sp1表达对RBP 2和其他JARID 1家族组蛋白脱甲基酶（包括PLU-1、SMCX和LSD 1）表达的抑制作用。此外，shRNA介导的I类HDAC同工酶1、2、3和8的沉默，而不是II类同工酶HDAC 6的沉默，模拟了药物对H3 K4甲基化和H3 K4脱甲基酶的作用，这可以通过异位Sp1表达逆转。这些数据表明，通过Sp1介导的转录调控，HDACs和H3 K4脱甲基酶之间的串扰机制，这是HDACs在组蛋白修饰调控中的功能作用的复杂性的基础。
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.