A key role for EZH2 in epigenetic silencing of HOX genes in mantle cell lymphoma
A key role for EZH2 in epigenetic silencing of HOX genes in mantle cell lymphoma
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DOI：
10.4161/epi.26546
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发表时间：
2013-12-01
期刊：
影响因子：
3.7
通讯作者：
Rosenquist, Richard
中科院分区：
文献类型：
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作者：
Kanduri, Meena;Sander, Birgitta;Rosenquist, Richard
染色质修饰物EZH2过表达与套细胞淋巴瘤(MCL)的预后不良有关。最近，与慢性淋巴细胞白血病(CLL)相比，我们发现在MCL中HOX基因的DNA甲基化优先，尽管这些基因在两种实体中都不表达。由于EZH2已被证明调控HOX基因的表达，为了进一步了解其在MCL和CLL中HOX基因差异沉默中的可能作用，我们使用具有代表性的细胞系和原代样本进行了详细的表观遗传学表征。我们观察到EZH2在MCL和CLL中显著过表达。染色质免疫沉淀(ChIP)分析表明，EZH2催化抑制性H3赖氨酸27三甲基化(H3K27me3)，足以沉默CLL中的Hox基因，而在MCL中H3K27me3伴随DNA甲基化以实现更稳定的抑制。更重要的是，在MCL中，HOX基因的高甲基化是由于EZH2的过度表达和随后DNA甲基化机制在HOX基因启动子上的招募所致。SiRNA转染和EZH2抑制剂实验进一步强调了EZH2上调在这一过程中的重要性。总之，这些观察结果表明，EZH2参与了MCL中HOX基因的长期沉默，并暗示了其作为具有临床影响的治疗靶点的潜力。
The chromatin modifier EZH2 is overexpressed and associated with inferior outcome in mantle cell lymphoma (MCL). Recently, we demonstrated preferential DNA methylation of HOX genes in MCL compared with chronic lymphocytic leukemia (CLL), despite these genes not being expressed in either entity. Since EZH2 has been shown to regulate HOX gene expression, to gain further insight into its possible role in differential silencing of HOX genes in MCL vs. CLL, we performed detailed epigenetic characterization using representative cell lines and primary samples. We observed significant overexpression of EZH2 in MCL vs. CLL. Chromatin immune precipitation (ChIP) assays revealed that EZH2 catalyzed repressive H3 lysine 27 trimethylation (H3K27me3), which was sufficient to silence HOX genes in CLL, whereas in MCL H3K27me3 is accompanied by DNA methylation for a more stable repression. More importantly, hypermethylation of the HOX genes in MCL resulted from EZH2 overexpression and subsequent recruitment of the DNA methylation machinery onto HOX gene promoters. The importance of EZH2 upregulation in this process was further underscored by siRNA transfection and EZH2 inhibitor experiments. Altogether, these observations implicate EZH2 in the long-term silencing of HOX genes in MCL, and allude to its potential as a therapeutic target with clinical impact.