Abnormal DNA methylation of CD133 in colorectal and glioblastoma tumors.
Abnormal DNA methylation of CD133 in colorectal and glioblastoma tumors.
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DOI：
10.1158/0008-5472.can-07-6208
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发表时间：
2008-10-01
期刊：
影响因子：
11.2
通讯作者：
Baylin SB
中科院分区：
文献类型：
--
作者：
Yi JM;Tsai HC;Glöckner SC;Lin S;Ohm JE;Easwaran H;James CD;Costello JF;Riggins G;Eberhart CG;Laterra J;Vescovi AL;Ahuja N;Herman JG;Schuebel KE;Baylin SB
最近的工作主要集中在鉴定和表征区分肿瘤增殖细胞（tpc）和更分化的后代的细胞标记物。我们在这里报告了一个不寻常的启动子DNA甲基化模式，其中一个这样的标记，细胞表面抗原CD133（突起1）。该蛋白已被广泛用于丰富上皮肿瘤，特别是胶质母细胞瘤中假定的癌症增殖干细胞样细胞群。我们发现，在培养的结肠癌和胶质母细胞瘤的单个细胞系中，CD133的启动子CpG岛是DNA甲基化的，主要是在标记蛋白缺乏或低表达的细胞中，而在纯CD133+细胞中缺乏这种甲基化是明显的。活性基因与抑制基因的差异组蛋白修饰标记伴随着这些DNA甲基化变化。肿瘤中这种异质CpG岛DNA甲基化状态是不寻常的，因为在这种培养中测试的其他DNA高甲基化基因在分离的CD133+和CD133−细胞群之间保持其甲基化模式。此外，CD133 DNA甲基化似乎构成了一个异常的启动子特征，因为它在正常的大脑和结肠中没有发现，而只在培养和原发性肿瘤中发现。因此，仅在肿瘤中，DNA甲基化作用于CD133的活性转录状态与抑制转录状态之间的转换。我们的发现为人类肿瘤中与异常基因沉默相关的异常DNA甲基化动力学提供了额外的见解。
Much recent effort has focused on identifying and characterizing cellular markers that distinguish tumor propagating cells (TPCs) from more differentiated progeny. We report here an unusual promoter DNA methylation pattern for one such marker, the cell surface antigen CD133 (Prominin 1). This protein has been extensively used to enrich putative cancer propagating stem-like cell populations in epithelial tumors, and especially, glioblastomas. We find that, within individual cell lines of cultured colon cancers and glioblastomas, the promoter CpG island of CD133 is DNA methylated, primarily, in cells with absent or low expression of the marker protein whereas lack of such methylation is evident in purely CD133+ cells. Differential histone modification marks of active versus repressed genes accompany these DNA methylation changes. This heterogeneous CpG island DNA methylation status in the tumors is unusual in that other DNA hypermethylated genes tested in such cultures preserve their methylation patterns between separated CD133+ and CD133− cell populations. Furthermore, the CD133 DNA methylation seems to constitute an abnormal promoter signature since it is not found in normal brain and colon but only in cultured and primary tumors. Thus, the DNA methylation is imposed on the transition between the active versus repressed transcription state for CD133 only in tumors. Our findings provide additional insight for the dynamics of aberrant DNA methylation associated with aberrant gene silencing in human tumors.