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

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.

Sohn BH ，Park IY ，Lee JJ ，Yang SJ ，Jang YJ ，Park KC ，Kim DJ ，Lee DC ，Sohn HA ，Kim TW ，Yoo HS ，Choi JY ，Bae YS ，Yeom YI ... -  《-》

Methylation of Tip30 promoter is associated with poor prognosis in human hepatocellular carcinoma.

Lu B ，Ma Y ，Wu G ，Tong X ，Guo H ，Liang A ，Cong W ，Liu C ，Wang H ，Wu M ，Zhao J ，Guo Y ... -  《CLINICAL CANCER RESEARCH》

Epidermal growth factor-containing fibulin-like extracellular matrix protein 1, EFEMP1, a novel tumor-suppressor gene detected in hepatocellular carcinoma using double combination array analysis.

Although hepatocellular carcinoma (HCC) is one of the commonest cancers worldwide, the underlying molecular mechanisms contributing to hepatocarcinogenesis are still not clear. In this study, we performed double array analysis, consisting of both expression profiling and karyotyping analysis using single-nucleotide polymorphism (SNP) array, of the same HCC sample from a 68-year-old woman with chronic hepatitis type C, and attempted to find a novel tumor-suppressor gene as a prognostic marker for HCC. According to the results of expression array, EFEMP1 gene, which has a role as an angiostatic molecule, showed decreased expression in tumor tissue. The copy number of chromosome 2, where EFEMP1 exists, 2p16, did not show chromosomal deletion. We found many CpG islands in the promoter region of EFEMP1 gene. Reactivation of EFEMP1 expression was seen on 5-aza-2'-deoxycytidine (5-aza-dC) treatment using HCC cell lines, and 24 of 48 (50%) HCC samples showed promoter hypermethylation. In the 24 methylated cases, most of the values of EFEMP1 gene expression examined by real-time reverse-transcription polymerase chain reaction (RT-PCR) in tumor tissues were significantly decreased (P = 0.0004). Intriguingly, EFEMP1 hypermethylation was significantly correlated with worse prognosis (P = 0.0271). Double array analysis revealed a novel tumor-suppressor gene, EFEMP1, for hepatocellular carcinoma. The mechanism for downregulation of EFEMP1 expression was closely associated with promoter hypermethylation. Promoter methylation of EFEMP1 gene was a marker of a worse prognosis in hepatocellular carcinoma.

Nomoto S ，Kanda M ，Okamura Y ，Nishikawa Y ，Qiyong L ，Fujii T ，Sugimoto H ，Takeda S ，Nakao A ... -  《-》

Silencing of caspase-8 in murine hepatocellular carcinomas is mediated via methylation of an essential promoter element.

Liedtke C ，Zschemisch NH ，Cohrs A ，Roskams T ，Borlak J ，Manns MP ，Trautwein C ... -  《GASTROENTEROLOGY》

Expression of mRNA for DNA methyltransferases and methyl-CpG-binding proteins and DNA methylation status on CpG islands and pericentromeric satellite regions during human hepatocarcinogenesis.

Saito Y ，Kanai Y ，Sakamoto M ，Saito H ，Ishii H ，Hirohashi S ... -  《HEPATOLOGY》