Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea.
Gastroenterology. 2010 May;138(5):1898-908. doi: 10.1053/j.gastro.2009.12.044. Epub 2009 Dec 29.
BACKGROUND & AIMS: Acquisition of resistance to the antiproliferative effect of transforming growth factor (TGF)-beta1 is crucial for the malignant progression of cancers. In this study, we sought to determine whether deregulated expression of tristetrapolin (TTP), a negative posttranscriptional regulator of c-Myc, confers resistance to the antiproliferative effects of TGF-beta1 on liver cancer cells.
The epigenetics of TTP promoter regulation and its effects on TGF-beta1 signaling were examined in hepatocellular carcinoma (HCC) cell lines and patient tissues.
TTP was down-regulated in HCC cell lines (10/11), compared with normal liver, as well as in tumor tissues (19/24) from paired HCC specimens. Methylation of a specific single CpG site located within the TGF-beta1-responsive region (TRR) of the TTP promoter was significantly associated with TTP down-regulation in both HCC cell lines and tumor tissues (r = -0.606383, P < .001). The singly methylated CpG site was specifically bound by a transcriptional repressor complex consisting of MECP2/c-Ski/DNMT3A and abolished the TGF-beta1-induced as well as basal-level expression of TTP. The epigenetic inactivation of TTP led to an increased half-life of c-Myc mRNA and blocked the cytostatic effect of TGF-beta1. Statistically significant correlations were observed between the single CpG site methylation and expression levels of TTP or c-Myc in clinical samples of HCC.
Abrogation of the post-transcriptional regulation of c-Myc via methylation of a specific single CpG site in the TTP promoter presents a novel mechanism for the gain of selective resistance to the antiproliferative signaling of TGF-beta1 in HCC.
获得对转化生长因子 (TGF)-β1 的抗增殖作用的抗性对于癌症的恶性进展至关重要。在这项研究中，我们试图确定 tristetrapolin（TTP）的表达失调是否赋予肝癌细胞对 TGF-β1 的抗增殖作用的抗性，TTP 是 c-Myc 的负转录后调节因子。
在肝癌细胞系和患者组织中检查 TTP 启动子调控的表观遗传学及其对 TGF-β1 信号转导的影响。
与正常肝组织相比，TTP 在肝癌细胞系（10/11）中下调，与配对 HCC 标本中的肿瘤组织（19/24）相比也是如此。位于 TTP 启动子 TGF-β1 反应区（TRR）内的特定单个 CpG 位点的甲基化与 HCC 细胞系和肿瘤组织中 TTP 的下调显著相关（r = -0.606383，P <.001）。该单一甲基化 CpG 位点被由 MECP2/c-Ski/DNMT3A 组成的转录抑制复合物特异性结合，并消除了 TGF-β1 诱导的以及基础水平的 TTP 表达。TTP 的表观遗传失活导致 c-Myc mRNA 的半衰期增加，并阻断了 TGF-β1 的细胞抑制作用。在 HCC 的临床样本中观察到单个 CpG 位点甲基化与 TTP 或 c-Myc 的表达水平之间存在显著相关性。
通过在 TTP 启动子中的特定单个 CpG 位点的甲基化破坏 c-Myc 的转录后调节，为 HCC 中对 TGF-β1 的抗增殖信号获得选择性抗性提供了一种新的机制。
