The histone acetyltransferase p300 inhibitor C646 reduces pro-inflammatory gene expression and inhibits histone deacetylases

组蛋白乙酰转移酶 乙酰化 组蛋白 组蛋白乙酰转移酶 P300-CBP转录因子 组蛋白脱乙酰基酶 组蛋白甲基转移酶 PCAF公司 生物 组蛋白H3 组蛋白H2A HDAC4型 乙酰转移酶 组蛋白脱乙酰基酶2 HDAC10型 组蛋白脱乙酰基酶5 信号转导 EZH2型 基因表达 SAP30型 化学 曲古抑菌素A 组蛋白脱乙酰酶抑制剂 表观遗传学 染色质免疫沉淀 细胞生物学 HDAC11型 染色质 生物化学 基因
作者
Thea van den Bosch,Alexander P. Boichenko,Niek G. J. Leus,Maria Eleni Ourailidou,Hannah Wapenaar,Dante Rotili,Antonello Mai,Axel Imhof,Rainer Bischoff,Hidde J. Haisma,Frank J. Dekker
出处
期刊:Biochemical Pharmacology [Elsevier]
卷期号:102: 130-140 被引量:48
标识
DOI:10.1016/j.bcp.2015.12.010
摘要

Lysine acetylations are reversible posttranslational modifications of histone and non-histone proteins that play important regulatory roles in signal transduction cascades and gene expression. Lysine acetylations are regulated by histone acetyltransferases as writers and histone deacetylases as erasers. Because of their role in signal transduction cascades, these enzymes are important players in inflammation. Therefore, histone acetyltransferase inhibitors could reduce inflammatory responses. Among the few histone acetyltransferase inhibitors described, C646 is one of the most potent (Ki of 0.4 μM for histone acetyltransferase p300). C646 was described to affect the NF-κB pathway; an important pathway in inflammatory responses, which is regulated by acetylation. This pathway has been implicated in asthma and COPD. Therefore, we hypothesized that via regulation of the NF-κB signaling pathway, C646 can inhibit pro-inflammatory gene expression, and have potential for the treatment of inflammatory lung diseases. In line with this, we demonstrate here that C646 reduces pro-inflammatory gene expression in RAW264.7 murine macrophages and murine precision-cut lung slices. To unravel its effects on cellular substrates we applied mass spectrometry and found, counterintuitively, a slight increase in acetylation of histone H3. Based on this finding, and structural features of C646, we presumed inhibitory activity of C646 on histone deacetylases, and indeed found inhibition of histone deacetylases from 7 μM and higher concentrations. This indicates that C646 has potential for further development towards applications in the treatment of inflammation, however, its newly discovered lack of selectivity at higher concentrations needs to be taken into account.
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