Epigenomic profiling reveals novel and frequent targets of aberrant DNA methylation-mediated silencing in malignant glioma
Epigenomic profiling reveals novel and frequent targets of aberrant DNA methylation-mediated silencing in malignant glioma
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DOI：
10.1158/0008-5472.can-05-4552
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发表时间：
2006-08-01
期刊：
影响因子：
11.2
通讯作者：
Robertson, Keith D.
中科院分区：
文献类型：
--
作者：
Kim, Tae-You;Zhong, Sheng;Robertson, Keith D.
恶性神经胶质瘤是成人最常见的中枢神经系统肿瘤，其发病率和死亡率都很高。神经胶质瘤具有高度侵袭性，对常规治疗反应不佳。神经胶质瘤，像其他肿瘤类型一样，是由一系列复杂且知之甚少的遗传和表观遗传改变引起的。导致基因沉默的表观遗传学改变，在异常的CpG岛启动子高甲基化和组蛋白脱乙酰化的形式，尚未在脑肿瘤中进行彻底的研究，阐明这种变化可能会提高我们对其病因的理解，并提供新的治疗选择。我们使用了一种结合药物抑制DNA甲基化和组蛋白去乙酰化的方法，再加上表达微阵列，以确定胶质瘤细胞系中表观遗传沉默的新靶点。从该分析中，我们鉴定了> 160个被5-氮杂-2 '-脱氧胞苷和阿司他汀A处理上调的基因。进一步表征这些基因中的10个，包括推定的转移抑制因子CST 6、肿瘤增殖诱导因子BIK和TSPYL 5（其功能未知），揭示它们是神经胶质瘤细胞系和原发性肿瘤中表观遗传沉默的常见靶标，并抑制培养物中的神经胶质瘤细胞生长。此外，我们表明，TSPYL基因家族的其他成员在神经胶质瘤中表观遗传沉默，并剖析个别DNA甲基转移酶的异常启动子超甲基化事件的贡献。因此，这些研究为全面了解胶质瘤表观遗传变化的全部程度以及如何将其用于治疗目的奠定了基础。
Malignant glioma is the most common central nervous system tumor of adults and is associated with a significant degree of morbidity and mortality. Gliomas are highly invasive and respond poorly to conventional treatments. Gliomas, like other tumor types, arise from a complex and poorly understood sequence of genetic and epigenetic alterations. Epigenetic alterations leading to gene silencing, in the form of aberrant CpG island promoter hypermethylation and histone deacetylation, have not been thoroughly investigated in brain tumors, and elucidating such changes is likely to enhance our understanding of their etiology and provide new treatment options. We used a combined approach of pharmacologic inhibition of DNA methylation and histone deacetylation, coupled with expression microarrays, to identify novel targets of epigenetic silencing in glioma cell lines. From this analysis, we identified > 160 genes up-regulated by 5-aza-2 '-deoxycytidine and trichostatin A treatment. Further characterization of 10 of these genes, including the putative metastasis suppressor CST6, the apoptosis-inducer BIK, and TSPYL5, whose function is unknown, revealed that they are frequent targets of epigenetic silencing in glioma cell lines and primary tumors and suppress glioma cell growth in culture. Furthermore, we show that other members of the TSPYL gene family are epigenetically silenced in gliomas and dissect the contribution of individual DNA methyltransferases to the aberrant pro moter hypermethylation events. These studies, therefore, lay the foundation for a comprehensive understanding of the full extent of epigenetic changes in gliomas and how they may be exploited for therapeutic purposes.