Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Sci Rep. 2012;2:592. doi: 10.1038/srep00592. Epub 2012 Aug 21.
Recent reports on direct reprogramming of cancer cells (iPCs) which results in reduced tumorigenic potential has attributed the importance of epigenetics in tumorigenesis, but lacked genome-wide analysis. Here we describe successful generation of iPCs from non-small cell lung cancer (NSCLC) cell lines. Following reprogramming, they resembled embryonic stem and induced pluripotent stem cells in pluripotency markers expression, gene expression patterns and in vitro differentiation ability. Genome-wide methylation analysis revealed that aberrantly methylated promoters which were mostly developmental-associated genes and tumor suppressors; as well as commonly upregulated genes in NSCLC i.e. KRT19 and S100P were reversed in iPCs upon reprogramming. Also, the reversal of oncogenes and tumor suppressors status were partially explainable by DNA methylation. These findings suggest that DNA methylation patterns explain the downstream transcriptional effects, which potentially caused the reduced tumorigenicity in iPCs, thus providing evidence that reprogramming reverses the aberrantly dysregulated genes in NSCLC both epigenetically and transcriptionally.
最近有研究报告称，通过直接重编程癌细胞（iPCs）可以降低肿瘤发生的潜力，这归因于表观遗传学在肿瘤发生中的重要性，但缺乏全基因组分析。在这里，我们描述了成功地从非小细胞肺癌（NSCLC）细胞系中生成 iPCs。在重编程后，它们在多能性标记物表达、基因表达模式和体外分化能力方面类似于胚胎干细胞和诱导多能干细胞。全基因组甲基化分析显示，异常甲基化的启动子主要是发育相关基因和肿瘤抑制基因；以及在 NSCLC 中普遍上调的基因，如 KRT19 和 S100P，在 iPCs 中重编程后被逆转。此外，癌基因和肿瘤抑制基因状态的逆转部分可以通过 DNA 甲基化来解释。这些发现表明，DNA 甲基化模式解释了下游转录效应，这可能导致 iPCs 中肿瘤发生性降低，从而提供了证据表明重编程在表观遗传和转录水平上逆转了 NSCLC 中异常失调的基因。
