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首页> 外文期刊>Journal of Molecular Biology >Cancer-associated 2-oxoglutarate analogues modify histone methylation by inhibiting histone lysine demethylases
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Cancer-associated 2-oxoglutarate analogues modify histone methylation by inhibiting histone lysine demethylases

机译：通过抑制组蛋白赖氨酸脱甲基酶来改变组蛋白甲基化的癌症相关的2-氧杂氮酸酯类似物

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Histone lysine demethylases (KDMs) are 2-oxoglutarate-dependent dioxygenases (2-OGDDs) that regulate gene expression by altering chromatin structure. Their dysregulation has been associated with many cancers. We set out to study the catalytic and inhibitory properties of human KDM4A, KDM4B, KDM5B, KDM6A and KDM6B, aiming in particular to reveal which of these enzymes are targeted by cancer-associated 2-oxoglutarate (2-OG) analogues. We used affinity-purified insect cell-produced enzymes and synthetic peptides with trimethylated lysines as substrates for the in vitro enzyme activity assays. In addition, we treated breast cancer cell lines with cell-permeable forms of 2-OG analogues and studied their effects on the global histone methylation state. Our data show that KDMs have substrate specificity. Among the enzymes studied, KDM5B had the highest affinity for the peptide substrate but the lowest affinity for the 2-OG and the Fe2+ cosubstrate/cofactors. R-2-hydroxyglutarate (R-2HG) was the most efficient inhibitor of KDM6A, KDM4A and KDM4B, followed by S-2HG. This finding was supported by accumulations of the histone H3K9me3 and H3K27me3 marks in cells treated with the cell-permeable forms of these compounds. KDM5B was especially resistant to inhibition by R-2HG, while citrate was the most efficient inhibitor of KDM6B. We conclude that KDM catalytic activity is susceptible to inhibition by tumorigenic 2-OG analogues and suggest that the inhibition of KDMs is involved in the disease mechanism of cancers in which these compounds accumulate, such as the isocitrate dehydrogenase mutations. (C) 2018 Elsevier Ltd. All rights reserved.
机译：组蛋白赖氨酸去甲基酶（KDMS）是通过改变染色质结构来调节基因表达的2-氧基氟化萘依赖性二恶氧基酶（2-OGDDS）。他们的失调已经与许多癌症有关。我们开始研究人KDM4A，KDM4B，KDM5B，KDM6A和KDM6B的催化和抑制性质，尤其揭示这些酶中的哪一项患有癌症相关的2-氧代或2-OG）类似物。我们将亲和性纯化的昆虫细胞产生的酶和合成肽用三甲基化赖氨酸作为用于体外酶活性测定的底物。此外，我们处理乳腺癌细胞系具有细胞可渗透形式的2-OG类似物，并研究其对全局组蛋白甲基化状态的影响。我们的数据显示KDMS具有底物特异性。在所研究的酶中，KDM5B对肽底物具有最高的亲和力，但是对于2-OG和Fe2 +宇烷体/辅因子的最低亲和力。 R-2-羟基戊酸酯（R-2Hg）是KDM6A，KDM4A和KDM4B中最有效的抑制剂，其次是S-2HG。通过这些化合物的细胞可渗透形式处理的细胞中的组蛋白H3k9me3和H3K27Me3标记的累积支持该发现。 KDM5B对R-2HG的抑制特别耐受，而柠檬酸盐是KDM6B最有效的抑制剂。我们得出结论，KDM催化活性易受致瘤2-OG类似物抑制的影响，并表明KDMS的抑制涉及这些化合物积聚的癌症的疾病机制，例如异柠檬酸脱氢酶突变。 （c）2018年elestvier有限公司保留所有权利。

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