TGF-β induces global changes in DNA methylation during the epithelial-to-mesenchymal transition in ovarian cancer cells
TGF-β induces global changes in DNA methylation during the epithelial-to-mesenchymal transition in ovarian cancer cells
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DOI：
10.4161/15592294.2014.971608
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发表时间：
2014-11-01
期刊：
影响因子：
3.7
通讯作者：
Matei, Daniela
中科院分区：
文献类型：
--
作者：
Cardenas, Horacio;Vieth, Edyta;Matei, Daniela
转移过程中的一个关键步骤是上皮向间充质转化(EMT)。我们假设表观遗传机制在EMT中起关键作用，为了验证这一假设，我们分析了转化生长因子诱导的卵巢癌细胞EMT过程中DNA甲基化的整体和基因特异性变化。使用Infinium Human Megylation450 BeadChip(HM450)的表观遗传学分析显示，在转化生长因子刺激后，广泛的(P<；0.01)甲基化改变(分别在细胞因子治疗后48小时和120小时改变了468和390个CpG位点)。大多数基因特异性的转化生长因子诱导的甲基化改变发生在启动子内或附近的CpG岛上(分别有193和494个基因在转化生长因子刺激后48小时和120小时发生甲基化)。此外，甲基化改变在转化生长因子治疗期间持续存在，并在细胞因子去除后可逆。对高甲基化基因座的路径分析确定了与EMT和癌症进展密切相关的功能网络，包括细胞运动、细胞周期、器官形态、细胞发育以及细胞死亡和存活。在转化生长因子诱导的EMT过程中，甲基化改变和相应的特定基因的表达包括CDH1(E-钙粘素)和COL1A1(胶原1A1)。此外，转化生长因子可诱导DNA甲基转移酶(DNMT)-1、-3A和-3B的表达和活性，DNMT抑制剂SGI-110可阻止转化生长因子诱导的内皮细胞转化。这些结果表明，DNA甲基组的动态变化与转化生长因子诱导的内胚层转移和转移有关。我们认为，靶向DNMT可能通过逆转癌症中被DNA甲基化沉默的EMT基因来抑制这一过程。
A key step in the process of metastasis is the epithelial-to-mesenchymal transition (EMT). We hypothesized that epigenetic mechanisms play a key role in EMT and to test this hypothesis we analyzed global and gene-specific changes in DNA methylation during TGF--induced EMT in ovarian cancer cells. Epigenetic profiling using the Infinium HumanMethylation450 BeadChip (HM450) revealed extensive (P < 0.01) methylation changes after TGF- stimulation (468 and 390 CpG sites altered at 48 and 120h post cytokine treatment, respectively). The majority of gene-specific TGF--induced methylation changes occurred in CpG islands located in or near promoters (193 and 494 genes hypermethylated at 48 and 120h after TGF- stimulation, respectively). Furthermore, methylation changes were sustained for the duration of TGF- treatment and reversible after the cytokine removal. Pathway analysis of the hypermethylated loci identified functional networks strongly associated with EMT and cancer progression, including cellular movement, cell cycle, organ morphology, cellular development, and cell death and survival. Altered methylation and corresponding expression of specific genes during TGF--induced EMT included CDH1 (E-cadherin) and COL1A1 (collagen 1A1). Furthermore, TGF- induced both expression and activity of DNA methyltransferases (DNMT) -1, -3A, and -3B, and treatment with the DNMT inhibitor SGI-110 prevented TGF--induced EMT. These results demonstrate that dynamic changes in the DNA methylome are implicated in TGF--induced EMT and metastasis. We suggest that targeting DNMTs may inhibit this process by reversing the EMT genes silenced by DNA methylation in cancer.