文章：

SUV39H1抑制剂毛壳菌素可诱导急性髓系白血病细胞分化，并与其他表观遗传药物表现出协同细胞毒性

The SUV39H1 inhibitor chaetocin induces differentiation and shows synergistic cytotoxicity with other epigenetic drugs in acute myeloid leukemia cells

原文发布日期：2015-05-15

DOI: 10.1038/bcj.2015.37

类型: Original Article

开放获取: 是

英文摘要：

Epigenetic modifying enzymes have a crucial role in the pathogenesis of acute myeloid leukemia (AML). Methylation of lysine 9 on histone H3 by the methyltransferase G9a and SUV39H1 is associated with inhibition of tumor suppressor genes. We studied the effect of G9a and SUV39H1 inhibitors on viability and differentiation of AML cells and tested the cytotoxicity induced by combination of G9a and SUV39H1 inhibitors and various epigenetic drugs. The SUV39H1 inhibitor (chaetocin) and the G9a inhibitor (UNC0638) caused cell death in AML cells at high concentrations. However, only chaetocin-induced CD11b expression and differentiation of AML cells at non-cytotoxic concentration. HL-60 and KG-1a cells were more sensitive to chaetocin than U937 cells. Long-term incubation of chaetocin led to downregulation of SUV39H1 and reduction of H3K9 tri-methylation in HL-60 and KG-1a cells. Combination of chaetocin with suberoylanilide hydroxamic acid (SAHA, a histone deacetylase inhibitor) or JQ (a BET (bromodomain extra terminal) bromodomain inhibitor) showed synergistic cytotoxicity. Conversely, no synergism was found by combining chaetocin and UNC0638. More importantly, chaetocin-induced differentiation and combined cytotoxicity were also found in the primary cells of AML patients. Collectively, the SUV39H1 inhibitor chaetocin alone or in combination with other epigenetic drugs may be effective for the treatment of AML.

摘要翻译： 

表观遗传修饰酶在急性髓系白血病（AML）的发病机制中起着关键作用。组蛋白H3上赖氨酸9的甲基化由甲基转移酶G9a和SUV39H1催化，与肿瘤抑制基因的抑制相关。我们研究了G9a和SUV39H1抑制剂对AML细胞活力和分化的影响，并测试了G9a与SUV39H1抑制剂联合多种表观遗传药物诱导的细胞毒性。高浓度下，SUV39H1抑制剂（chaetocin）和G9a抑制剂（UNC0638）均导致AML细胞死亡。然而，仅在非细胞毒性浓度下，chaetocin能诱导CD11b表达和AML细胞分化。HL-60和KG-1a细胞对chaetocin的敏感性高于U937细胞。长期孵育chaetocin导致HL-60和KG-1a细胞中SUV39H1下调和H3K9三甲基化减少。Chaetocin与伏立诺他（SAHA，一种组蛋白去乙酰化酶抑制剂）或JQ（一种BET溴结构域抑制剂）联用显示出协同细胞毒性。相反，chaetocin与UNC0638联合未产生协同效应。更重要的是，在AML患者原代细胞中也观察到chaetocin诱导的分化及联合细胞毒性作用。综上所述，SUV39H1抑制剂chaetocin单独或与其他表观遗传药物联合使用可能对AML治疗有效。

原文链接：

The SUV39H1 inhibitor chaetocin induces differentiation and shows synergistic cytotoxicity with other epigenetic drugs in acute myeloid leukemia cells