A Novel Histone Acetyltransferase Inhibitor Modulating Gcn5 Network: Cyclopentylidene-[4-(4′-chlorophenyl)thiazol-2-yl)hydrazone
A Novel Histone Acetyltransferase Inhibitor Modulating Gcn5 Network: Cyclopentylidene-[4-(4′-chlorophenyl)thiazol-2-yl)hydrazone
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DOI：
10.1021/jm800885d
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发表时间：
2009-01-22
影响因子：
7.3
通讯作者：
Filetici, Patrizia
中科院分区：
文献类型：
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作者：
Chimenti, Franco;Bizzarri, Bruna;Filetici, Patrizia
乙酰化是通过去凝集染色质结构来调节基因组可及性的关键因素。事实上，乙酰化和相对去乙酰化之间的平衡是一些细胞功能和分化的先决条件。为了寻找历史上的乙酰转移酶Gcn5p的调节子，我们对一组新合成的来自噻唑的分子在发芽酵母酿酒酵母中进行了表型筛选。我们选择了在编码组蛋白乙酰转移酶基因缺失的酵母菌株中诱导生长抑制的化合物。基于其对gcn5Delta菌株生长的抑制作用，选择了一种新的分子cyclopentylidene-[4-(4‘-chlorophenyl)thiazol2-yl)hydrazone，。我们证明了CPTH2与HAT Gcn5p之间存在特异性的化学遗传相互作用，表明CPTH2抑制了Gcn5p依赖的功能网络。CPTH2抑制体外HAT反应，该反应可通过增加组蛋白H3的浓度而逆转。在体内，它减少了组蛋白H3在特定的H3-AcK14位点的乙酰化。综上所述，我们的结果表明CPTH2是一种新型的HAT抑制剂，在体内外调节Gcn5p网络。
Acetylation is a key modulator of genome accessibility through decondensation of the chromatin structure. The balance between acetylation and opposite deacetylation is, in fact, a prerequisite for several cell functions and differentiation. To find modulators of the historic acetyltransferase Gcn5p, we performed a phenotypic screening on a set of newly synthesized molecules derived from thiazole in budding yeast Saccharomyces cerevisiae. We selected compounds that induce growth inhibition in yeast strains deleted in genes encoding known histone acetyltransferases. A novel molecule CPTH2, cyclopentylidene-[4-(4'-chlorophenyl)thiazol2-yl)hydrazone, was selected based on its inhibitory effect on the growth of a gcn5 Delta strain. We demonstrated a specific chemical-genetic interaction between CPTH2 and HAT Gcn5p, indicating that CPTH2 inhibits the Gcn5p dependent functional network. CPTH2 inhibited an in vitro HAT reaction, which is reverted by increasing concentration of histone H3. In vivo, it decreased acetylation of bulk histone H3 at the specific H3-AcK14 site. On the whole, our results demonstrate that CPTH2 is a novel HAT inhibitor modulating Gcn5p network in vitro and in vivo.