The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Bunting Blaustein Bldg, Room 551, 1650 Orleans Street, Baltimore, MD, 21287, USA.
Amino Acids. 2014 Mar;46(3):585-94. doi: 10.1007/s00726-013-1485-1. Epub 2013 Mar 19.
Aberrant epigenetic silencing of tumor suppressor genes is a common feature observed during the transformation process of many cancers, including those of hematologic origin. Histone modifications, including acetylation, phosphorylation, and methylation, collaborate with DNA CpG island methylation to regulate gene expression. The dynamic process of histone methylation is the latest of these epigenetic modifications to be described, and the identification and characterization of LSD1 as a demethylase of lysine 4 of histone H3 (H3K4) has confirmed that both the enzyme and the modified histone play important roles as regulators of gene expression. LSD1 activity contributes to the suppression of gene expression by demethylating promoter-region mono- and dimethyl-H3K4 histone marks that are associated with active gene expression. As most post-translational modifications are reversible, the enzymes involved in the modification of histones have become targets for chemotherapeutic intervention. In this study, we examined the effects of the polyamine analogue LSD1 inhibitor 2d (1,15-bis{N (5)-[3,3-(diphenyl)propyl]-N(1)-biguanido}-4,12-diazapentadecane) in human acute myeloid leukemia (AML) cell lines. In each line studied, 2d evoked cytotoxicity and inhibited LSD1 activity, as evidenced by increases in the global levels of mono- and di-methylated H3K4 proteins. Global increases in other chromatin modifications were also observed following exposure to 2d, suggesting a broad response to this compound with respect to chromatin regulation. On a gene-specific level, treatment with 2d resulted in the re-expression of e-cadherin, a tumor suppressor gene frequently silenced by epigenetic modification in AML. Quantitative chromatin immunoprecipitation analysis of the e-cadherin promoter further confirmed that this re-expression was concurrent with changes in both active and repressive histone marks that were consistent with LSD1 inhibition. As hematologic malignancies have demonstrated promising clinical responses to agents targeting epigenetic silencing, this polyamine analogue LSD1 inhibitor presents an exciting new avenue for the development of novel therapeutic agents for the treatment of AML.
肿瘤抑制基因的表观遗传沉默是许多癌症（包括血液来源的癌症）转化过程中的一个常见特征。组蛋白修饰，包括乙酰化、磷酸化和甲基化，与 DNA CpG 岛甲基化一起调节基因表达。组蛋白甲基化的动态过程是最近描述的这些表观遗传修饰之一，并且 LSD1 作为组蛋白 H3（H3K4）赖氨酸 4 的去甲基酶的鉴定和表征已证实，酶和修饰的组蛋白都作为基因表达的调节剂发挥重要作用。LSD1 活性通过去甲基化与活性基因表达相关的启动子区域单甲基和二甲基 H3K4 组蛋白标记来抑制基因表达。由于大多数翻译后修饰是可逆的，因此参与组蛋白修饰的酶已成为化学治疗干预的靶标。在这项研究中，我们研究了多胺类似物 LSD1 抑制剂 2d（1,15-双{[3,3-（二苯基）丙基]-N（1）-双胍基}-4,12-二氮杂十五烷）在人急性髓系白血病（AML）细胞系中的作用。在研究的每条系中，2d 引起细胞毒性并抑制 LSD1 活性，这表现为单甲基和二甲基 H3K4 蛋白的整体水平增加。暴露于 2d 后还观察到其他染色质修饰的整体增加，这表明对该化合物在染色质调节方面有广泛的反应。在基因特异性水平上，用 2d 处理导致肿瘤抑制基因 E-钙粘蛋白的重新表达，E-钙粘蛋白在 AML 中经常因表观遗传修饰而沉默。E-钙粘蛋白启动子的定量染色质免疫沉淀分析进一步证实，这种重新表达与 LSD1 抑制一致的活性和抑制性组蛋白标记的变化同时发生。由于血液恶性肿瘤对靶向表观遗传沉默的药物表现出有希望的临床反应，因此这种多胺类似物 LSD1 抑制剂为开发用于治疗 AML 的新型治疗剂提供了令人兴奋的新途径。
