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

Title
Functional Switching of TGF-β1 Signaling in Liver Cancer via Epigenetic Modulation of a Single CpG Site in TTP Promoter
Authors
Sohn B.H.Park I.Y.Lee J.J.Yang S.Jang Y.J.Park K.C.Kim D.J.Lee D.C.Sohn H.A.Kim T.W.Yoo H.Choi J.Y.Bae Y.S.Yeom Y.I.
Ewha Authors
배윤수
SCOPUS Author ID
배윤수scopus
Issue Date
2010
Journal Title
Gastroenterology
ISSN
0016-5085JCR Link
Citation
vol. 138, no. 5, pp. 1898 - 1908000000000000
Indexed
SCI; SCIE; SCOPUS WOS scopus
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. © 2010 AGA Institute.
DOI
10.1053/j.gastro.2009.12.044
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자연과학대학 > 생명과학전공 > Journal papers
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