Inhibition of Euchromatic Histone Methyltransferase 1 and 2 Sensitizes Chronic Myeloid Leukemia Cells to Interferon Treatment

Background
H3K9 methylation is one of the essential histone post-translational modifications for heterochromatin formation and transcriptional repression. Recently, several studies have demonstrated that H3K9 methylation negatively regulates the type I interferon response.
Results
We report the application of EHMT1 and EHMT2 specific chemical inhibitors to sensitize CML cell lines to interferon and imatinib treatments. Inhibition of EHMT1 and EHMT2 with BIX01294 enhances the cytotoxicity of IFNα2a in four CML cell lines, K562, KCL22, BV173 and KT1 cells. Chromatin immunoprecipitation assay shows that BIX01294 treatment enhances type I interferon response by reducing H3K9me2 at the promoters of interferon-stimulated genes. Additionally, BIX01294 treatment augments IFNα2a- and imatinib-mediated apoptosis in CML cell lines. Moreover, our data suggest that the expression level of EHMT1 and EHMT2 inversely correlates with the type I interferon responsiveness in CML cell lines.
Conclusions
Our study sheds light on the role of EHMT1 and EHMT2 as potential targets in improving the efficacy of standard treatments of CML.

背景
H3K9甲基化是参与异染色质形成与转录抑制的关键组蛋白翻译后修饰之一。近期多项研究证实，H3K9甲基化可负调控I型干扰素应答。

结果
本研究报道了利用组蛋白赖氨酸甲基转移酶1（EHMT1）和组蛋白赖氨酸甲基转移酶2（EHMT2）的特异性化学抑制剂，使慢性髓系白血病（Chronic Myeloid Leukemia, CML）细胞系对干扰素与伊马替尼治疗增敏的应用。通过BIX01294抑制EHMT1与EHMT2的活性，可增强干扰素α2a（Interferon α2a, IFNα2a）在K562、KCL22、BV173及KT1这四种CML细胞系中的细胞毒性。染色质免疫沉淀（Chromatin Immunoprecipitation, ChIP）实验结果显示，BIX01294处理可通过降低干扰素刺激基因（Interferon-stimulated genes, ISGs）启动子区域的H3K9me2水平，增强I型干扰素应答。此外，BIX01294处理可进一步增强CML细胞系中干扰素α2a与伊马替尼介导的细胞凋亡。本研究数据还表明，CML细胞系中EHMT1与EHMT2的表达水平与I型干扰素应答呈负相关。

结论
本研究揭示了EHMT1和EHMT2作为潜在靶点，在提升慢性髓系白血病标准治疗疗效中的重要作用。