Functional switching of TGF-beta1 signaling in liver cancer via epigenetic modulation of a single CpG site in TTP promoter

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Title
Functional switching of TGF-beta1 signaling in liver cancer via epigenetic modulation of a single CpG site in TTP promoter
Author(s)
Bo Hwa Son; In Young Park; J J Lee; Suk Jin Yang; Yeo-jin Jang; Kyung Chan Park; D J Kim; Dong Chul Lee; Hyun Ahm Sohn; Tae Woo Kim; Hyang Sook Yoo; J Y Choi; Y S Bae; Young Il Yeom
Bibliographic Citation
Gastroenterology, vol. 138, no. 5, pp. 1898-1908
Publication Year
2010
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.
Keyword
HCCMethylationTGF-β1TTP
ISSN
0016-5085
Publisher
Elsevier
DOI
http://dx.doi.org/10.1053/j.gastro.2009.12.044
Type
Article
Appears in Collections:
Division of Biomedical Research > Personalized Genomic Medicine Research Center > 1. Journal Articles
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