Functional epigenomics identifies genes frequently silenced in prostate cancer
Functional epigenomics identifies genes frequently silenced in prostate cancer
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DOI：
10.1158/0008-5472.can-04-4407
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发表时间：
2005-05-15
期刊：
影响因子：
11.2
通讯作者：
Hermeking, H
中科院分区：
文献类型：
--
作者：
Lodygin, D;Epanchintsev, A;Hermeking, H
在许多情况下，CpG 甲基化导致的基因表达沉默与癌发生有关。此外，癌症特异性 CpG 甲基化可以作为肿瘤标志物。为了鉴定前列腺癌中因 CpG 甲基化而失活的候选基因，用 5-aza-2' 脱氧胞苷和曲古抑菌素 A 处理前列腺癌细胞系 LNCaP、PC3 和 Du-145，从而导致表观遗传沉默的逆转。通过对 18,400 个单独转录本的微阵列分析，发现与用曲古抑菌素 A 处理的细胞相比，数百个基因被诱导。根据已知的功能，选择了 50 个重新表达的基因进行进一步分析，这意味着可能参与肿瘤抑制。其中 12 个基因在其启动子中显示出显着程度的 CpG 甲基化。在五个分析的前列腺癌细胞系中，有六个基因被 CpG 甲基化沉默，尽管它们在从四个不同供体获得的正常前列腺上皮细胞中显示出强大的 mRNA 表达。在来自 41 名患者的原发性前列腺癌样本中，在这些基因的启动子区域检测到的 CpG 甲基化频率为：GPX3，93%； SFRP1，83%； COX2，78%；丹麦克朗3，68%； GSTM1，58%；和 KIP2/p57，56%。 SFRP1 或 DKK3 的异位表达导致增殖减少。 DKK3 的表达伴随着丝裂原激活蛋白激酶途径的减弱。在已识别基因的启动子中检测到的高频率 CpG 甲基化表明其与前列腺癌存在潜在因果关系，并且可能对诊断目的有用。
In many cases, silencing of gene expression by CpG methylation is causally involved in carcinogenesis. Furthermore, cancer-specific CpG methylation may serve as a tumor marker. In order to identify candidate genes for inactivation by CpG methylation in prostate cancer, the prostate cancer cell lines LNCaP, PC3, and Du-145 were treated with 5-aza-2' deoxycytidine and trichostatin A, which leads to reversion of epigenetic silencing. By microarray analysis of 18,400 individual transcripts, several hundred genes were found to be induced when compared with cells treated with trichostatin A. Fifty re-expressed genes were selected for further analysis based on their known function, which implied a possible involvement in tumor suppression. Twelve of these genes showed a significant degree of CpG methylation in their promoters. Six genes were silenced by CpG methylation in the majority of five analyzed prostate cancer cell lines, although they displayed robust mRNA expression in normal prostate epithelial cells obtained from four different donors. In primary prostate cancer samples derived from 41 patients, the frequencies of CpG methylation detected in the promoter regions of these genes were: GPX3, 93%; SFRP1, 83%; COX2, 78%; DKK3, 68%; GSTM1, 58%; and KIP2/p57, 56%. Ectopic expression of SFRP1 or DKK3 resulted in decreased proliferation. The expression of DKK3 was accompanied by attenuation of the mitogen-activated protein kinase pathway. The high frequency of CpG methylation detected in the promoters of the identified genes suggests a potential causal involvement in prostate cancer and may prove useful for diagnostic purposes.