Genetic unmasking of an epigenetically silenced microRNA in human cancer cells
Genetic unmasking of an epigenetically silenced microRNA in human cancer cells
复制标题
DOI：
10.1158/0008-5472.can-06-4218
复制
发表时间：
2007-02-15
期刊：
影响因子：
11.2
通讯作者：
Esteller, Manel
中科院分区：
文献类型：
--
作者：
Lujambio, Amaia;Ropero, Santiago;Esteller, Manel
人类疾病中microRNA（miRNA）破坏的潜在机制知之甚少。在癌细胞中，由CpG岛启动子超甲基化引起的肿瘤抑制基因的转录沉默已成为常见的标志。我们想知道是否同样的表观遗传破坏可以“击中”转化细胞中的miRNA。为了解决这个问题，我们使用了DNA甲基转移酶遗传缺陷的癌细胞与miRNA表达谱的组合。我们已经观察到DNA低甲基化诱导癌细胞中miRNA沉默的释放。主要靶点之一是miRNA-124 a，其在来自不同细胞类型的人类肿瘤中通过CpG岛超甲基化而经历转录失活。有趣的是，我们在功能上将miRNA-124 a的表观遗传丢失与细胞周期蛋白D激酶6（一种真正的致癌因子）的激活和视网膜母细胞瘤（一种肿瘤抑制基因）的磷酸化联系起来。
The mechanisms underlying microRNA (miRNA) disruption in human disease are poorly understood. In cancer cells, the transcriptional silencing of tumor suppressor genes by CpG island promoter hypermethylation has emerged as a common hallmark. We wondered if the same epigenetic disruption can "hit" miRNAs in transformed cells. To address this issue, we have used cancer cells genetically deficient for the DNA methyltransferase enzymes in combination with a miRNA expression profiling. We have observed that DNA hypomethylation induces a release of miRNA silencing in cancer cells. One of the main targets is miRNA-124a, which undergoes transcriptional inactivation by CpG island hypermethylation in human tumors from different cell types. Interestingly, we functionally link the epigenetic loss of miRNA-124a with the activation of cyclin D kinase 6, a bona fide oncogenic factor, and the phosphorylation of the retinoblastoma, a tumor suppressor gene.