Digging deep into "dirty" drugs - modulation of the methylation machinery.
Digging deep into "dirty" drugs - modulation of the methylation machinery.
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DOI：
10.3109/03602532.2014.995379
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发表时间：
2015-05
影响因子：
5.9
通讯作者：
Greil R
中科院分区：
文献类型：
--
作者：
Pleyer L;Greil R
DNA 甲基化和组蛋白修饰是导致基因表达和细胞表型改变的表观遗传机制。甲基化在骨髓增生异常综合征（MDS）和急性髓系白血病（AML）中的确切作用仍不清楚。然而，一般表观遗传转录调控成分的畸变（例如功能丧失/获得或上调/下调），特别是甲基化机制的畸变，与这些疾病的发病机制有关。此外，其中许多成分已被确定为 MDS/AML 患者的治疗靶点，并且也被评估为对低甲基化药物 (HMA) 反应或耐药的潜在生物标志物。 HMA 5-阿扎胞苷 (AZA) 和 2′-脱氧-5-阿扎胞苷（地西他滨，DAC）可抑制 DNA 甲基化，并在骨髓恶性肿瘤患者中显示出显着的临床益处。尽管 AZA 和 DAC 被视为机制相似的药物，但其作用机制不同。 DAC 100% 掺入 DNA，而 AZA 掺入 RNA (80-90%) 和 DNA (10-20%)。因此，这两种药物都会抑制 DNA 甲基转移酶（DNMT；依赖于或独立于 DNA 复制），从而导致肿瘤抑制基因的重新表达；然而，AZA 还通过抑制核糖核苷酸还原酶对 mRNA 和蛋白质代谢产生影响，导致细胞凋亡。在此，我们首先概述转录调控，包括 DNA 甲基化、翻译后组蛋白尾修饰、微小 RNA 的作用和长程表观遗传基因沉默。我们特别强调表观遗传转录调控，并讨论各种成分在 MDS/AML 发病机制中的含义、它们作为治疗靶点的潜力，以及 HMA 和其他物质（如果已知）对它们的治疗调节。本综述的主要重点是剖析 AZA 和 DAC 快速发展的知识，特别关注它们不同的作用机制以及 HMA 对转录调控的影响。
DNA methylation and histone modification are epigenetic mechanisms that result in altered gene expression and cellular phenotype. The exact role of methylation in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) remains unclear. However, aberrations (e.g. loss-/gain-of-function or up-/down-regulation) in components of epigenetic transcriptional regulation in general, and of the methylation machinery in particular, have been implicated in the pathogenesis of these diseases. In addition, many of these components have been identified as therapeutic targets for patients with MDS/AML, and are also being assessed as potential biomarkers of response or resistance to hypomethylating agents (HMAs). The HMAs 5-azacitidine (AZA) and 2′-deoxy-5-azacitidine (decitabine, DAC) inhibit DNA methylation and have shown significant clinical benefits in patients with myeloid malignancies. Despite being viewed as mechanistically similar drugs, AZA and DAC have differing mechanisms of action. DAC is incorporated 100% into DNA, whereas AZA is incorporated into RNA (80–90%) as well as DNA (10–20%). As such, both drugs inhibit DNA methyltransferases (DNMTs; dependently or independently of DNA replication) resulting in the re-expression of tumor-suppressor genes; however, AZA also has an impact on mRNA and protein metabolism via its inhibition of ribonucleotide reductase, resulting in apoptosis. Herein, we first give an overview of transcriptional regulation, including DNA methylation, post-translational histone-tail modifications, the role of micro-RNA and long-range epigenetic gene silencing. We place special emphasis on epigenetic transcriptional regulation and discuss the implication of various components in the pathogenesis of MDS/AML, their potential as therapeutic targets, and their therapeutic modulation by HMAs and other substances (if known). The main focus of this review is laid on dissecting the rapidly evolving knowledge of AZA and DAC with a special focus on their differing mechanisms of action, and the effect of HMAs on transcriptional regulation.
影响因子：
4.5
作者：
Kim MK;Lee JL;Cho HS;Bae SH;Ryoo HM;Lee KH;Hyun MS
通讯作者：
Hyun MS