Functional Switching of TGF-β1 Signaling in Liver Cancer via Epigenetic Modulation of a Single CpG Site in TTP Promoter

Bo Hwa Sohn, In Young Park, Jung Ju Lee, Suk Jin Yang, Ye Jin Jang, Kyung Chan Park, Dong Joon Kim, Dong Chul Lee, Hyun Ahm Sohn, Tae Woo Kim, Hyang Sook Yoo, Jong Young Choi, Yun Soo Bae, Young Il Yeom

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80 Scopus citations

Abstract

Background & Aims: Acquisition of resistance to the antiproliferative effect of transforming growth factor (TGF)-β1 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-β1 on liver cancer cells. Methods: The epigenetics of TTP promoter regulation and its effects on TGF-β1 signaling were examined in hepatocellular carcinoma (HCC) cell lines and patient tissues. Results: 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-β1-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-β1-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-β1. Statistically significant correlations were observed between the single CpG site methylation and expression levels of TTP or c-Myc in clinical samples of HCC. Conclusions: 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-β1 in HCC.

Original languageEnglish
Pages (from-to)1898-1908.e12
JournalGastroenterology
Volume138
Issue number5
DOIs
StatePublished - May 2010

Keywords

  • HCC
  • Methylation
  • TGF-β1
  • TTP

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