Overexpression of enhancer of zeste homolog 2 with trimethylation of lysine 27 on histone H3 in adult T-cell leukemia/lymphoma as a target for epigenetic therapy
Overexpression of enhancer of zeste homolog 2 with trimethylation of lysine 27 on histone H3 in adult T-cell leukemia/lymphoma as a target for epigenetic therapy
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DOI：
10.3324/haematol.2010.028605
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发表时间：
2011-05-01
期刊：
影响因子：
--
通讯作者：
Yamada, Yasuaki
中科院分区：
文献类型：
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作者：
Sasaki, Daisuke;Imaizumi, Yoshitaka;Yamada, Yasuaki
Zeste增强子同源物2是Polycomb抑制复合物2的一个组成部分，通过组蛋白H3上赖氨酸27的三甲基化介导基于染色质的基因沉默。该复合物在发育特异性基因表达的调节中起着至关重要的作用。设计和方法在这项研究中，进行了原发性成人T细胞白血病/淋巴瘤样品中基因表达的比较微阵列分析，结果Zeste同源物2增强子、RING 1和YY 1结合蛋白转录本水平显著升高，三甲基化水平升高，与正常CD 4（+）T细胞相比，成人T细胞白血病/淋巴瘤细胞组蛋白H3上赖氨酸27的表达明显增加。此外，zeste增强子同源物2的表达水平与miR-101或miR-128 a的表达水平之间存在负相关性，这表明后者miRNA的表达改变解释了前者的过表达。Zeste增强子同源物2或RING 1和YY 1结合蛋白转录物高表达的患者的预后显著差于无表达的患者，表明这些基因在该疾病的肿瘤发生和进展中可能起作用。事实上，成人T细胞白血病/淋巴瘤细胞对组蛋白甲基化抑制剂3-deazaneplanocin A敏感。3-deazaneplanocin A和组蛋白去乙酰化酶抑制剂panobinostat对T细胞白血病/淋巴瘤细胞有协同杀伤作用。结论这些发现揭示了成人T细胞白血病/淋巴瘤细胞具有去调节的Polycomb抑制复合物2和过表达的增强子zeste同源物2，并且有可能在这种疾病中以组蛋白甲基化为靶点的新的治疗策略。
BackgroundEnhancer of zeste homolog 2 is a component of the Polycomb repressive complex 2 that mediates chromatin-based gene silencing through trimethylation of lysine 27 on histone H3. This complex plays vital roles in the regulation of development-specific gene expression.Design and MethodsIn this study, a comparative microarray analysis of gene expression in primary adult T-cell leukemia/lymphoma samples was performed, and the results were evaluated for their oncogenic and clinical significance.ResultsSignificantly higher levels of Enhancr of zeste homolog 2 and RING1 and YY1 binding protein transcripts with enhanced levels of trimethylation of lysine 27 on histone H3 were found in adult T-cell leukemia/lymphoma cells compared with those in normal CD4(+) T cells. Furthermore, there was an inverse correlation between the expression level of Enhancer of zeste homolog 2 and that of miR-101 or miR-128a, suggesting that the altered expression of the latter miRNAs accounts for the overexpression of the former. Patients with high Enhancer of zeste homolog 2 or RING1 and YY1 binding protein transcripts had a significantly worse prognosis than those without it, indicating a possible role of these genes in the oncogenesis and progression of this disease. Indeed, adult T-cell leukemia/lymphoma cells were sensitive to a histone methylation inhibitor, 3-deazaneplanocin A. Furthermore, 3-deazaneplanocin A and histone deacetylase inhibitor panobinostat showed a synergistic effect in killing the cellsConclusionsThese findings reveal that adult T-cell leukemia/lymphoma cells have deregulated Polycomb repressive complex 2 with over-expressed Enhancer of zeste homolog 2, and that there is the possibility of a new therapeutic strategy targeting histone methylation in this disease.