Drug sensitivity prediction by CpG island methylation profile in the NCI-60 cancer cell line panel
Drug sensitivity prediction by CpG island methylation profile in the NCI-60 cancer cell line panel
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DOI：
10.1158/0008-5472.can-07-1502
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发表时间：
2007-12-01
期刊：
影响因子：
11.2
通讯作者：
Issa, Jean-Pierre J.
中科院分区：
文献类型：
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作者：
Shen, Lanlan;Kondo, Yutaka;Issa, Jean-Pierre J.
启动子异常甲基化和相关基因沉默是肿瘤发生的表观遗传学特征。已有研究表明，DNA甲基化异常可通过改变药物反应关键基因的表达来影响癌症对抗肿瘤药物的敏感性。为了研究这一问题，我们使用亚硫酸氢盐聚合酶链式反应来评估来自美国国家癌症研究所(NCI)药物筛选小组(NCI-60小组)的人类癌细胞系中启动子相关的CpG岛的DNA甲基化。在NCI-60癌细胞中，这些岛异常甲基化的频率从2%到81%不等，并提供了一个数据库，可以分析该小组测试的30,000种药物的敏感性。通过将药物活性与DNA甲基化相关联，我们确定了一系列甲基化标记物，这些标记物可以预测化疗药物的敏感性。其中，P53同源基因p73高甲基化和相关基因沉默与烷化药物敏感性密切相关。我们使用小干扰RNA下调了多个细胞系中p73的表达，包括耐药细胞系TK10(肾癌)和SKMEL28(黑色素瘤)。下调p73显著增加了对常用烷基化药物的敏感性，包括顺铂，这表明p73的表观遗传沉默直接调节了药物敏感性。我们的结果证实，表观遗传学图谱在确定癌症药物敏感性的分子介体(药物表观基因组学)方面是有用的。
Aberrant promoter hypermethylation and associated gene silencing are epigenetic hallmarks of tumorigenesis. It has been suggested that aberrant DNA methylation can affect the sensitivity of cancers to antineoplastic agents by altering expression of genes critical to drug response. To study this issue, we used bisulfite PCR to assess DNA methylation of promoter-associated CpG islands in human cancer cell lines from the National Cancer Institute (NCI) drug-screening panel (NCI-60 panel). The frequency of aberrant hypermethylation of these islands ranged from 2% to 81% in NCI-60 cancer cells, and provided a database that can be analyzed for the sensitivity to 30,000 drugs tested in this panel. By correlating drug activity with DNA methylation, we identified a list of methylation markers that predict sensitivity to chemotherapeutic drugs. Among them, hypermethylation of the p53 homologue p73 and associated gene silencing was strongly correlated with sensitivity to alkylating agents. We used small interfering RNA to down-regulate p73 expression in multiple cell lines, including the resistant cell lines TK10 (renal cancer) and SKMEL28 (melanoma). Down-regulating p73 substantially increased sensitivity to commonly used alkylating agents, including cisplatin, indicating that epigenetic silencing of p73 directly modulates drug sensitivity. Our results confirm that epigenetic profiles are useful in identifying molecular mediators for cancer drug sensitivity (pharmaco-epigenomics).