Hepatitis B virus X protein promotes hypermethylation of p16(INK4A) promoter through upregulation of DNA methyltransferases in hepatocarcinogenesis.

The hepatitis B virus×protein (HBx) has been implicated as a potential trigger of the epigenetic deregulation of some genes, but the underlying mechanism remains unknown. The aim of this study is to identify underlying mechanisms involved in HBx-mediated epigenetic modification in the process of HBx induced p16(INK4A) promoter hypermethylation. Liver cell lines were stably transfected with HBx-expressing vector. The methylation status of p16(INK4A) was examined by methyl-specific polymerase chain reaction (MSP) and bisulfite sequencing. Reverse transcription and real-time polymerase chain reaction (real-time RT-PCR), Western blot and immunohistochemistry were used to analyze the expression of HBx, HBx-mediated DNA methylation abnormalities and p16(INK4A). Some cases of HCC and corresponding noncancerous liver tissues were studied. HBx up-regulates DNMT1 and DNMT3A expression in both mRNA level and protein level, and HBx represses p16(INK4A) expression through inducing hypermethylation of p16(INK4A) promoter. Moreover, HBx induces hypermethylation of p16(INK4A) promoter through DNMT1 and DNMT3A. Regulation of DNMT1 and DNMT3A by HBx promoted hypermethylation of p16(INK4A) promoter region. HBx-DNMTs-p16(INK4A) promoter hypermethylation may suggest a mechanism for tumorigenesis during hepatocarcinogenesis.

Zhu YZ ，Zhu R ，Shi LG ，Mao Y ，Zheng GJ ，Chen Q ，Zhu HG ... -  《-》

Aberrant epigenetic modifications in hepatocarcinogenesis induced by hepatitis B virus X protein.

Park IY ，Sohn BH ，Yu E ，Suh DJ ，Chung YH ，Lee JH ，Surzycki SJ ，Lee YI ... -  《GASTROENTEROLOGY》

Hepatitis B virus X protein induces hypermethylation of p16(INK4A) promoter via DNA methyltransferases in the early stage of HBV-associated hepatocarcinogenesis.

Zhu YZ ，Zhu R ，Fan J ，Pan Q ，Li H ，Chen Q ，Zhu HG ... -  《-》

Association of p16INK4A hypermethylation with hepatitis B virus X protein expression in the early stage of HBV-associated hepatocarcinogenesis.

Zhu R ，Li BZ ，Li H ，Ling YQ ，Hu XQ ，Zhai WR ，Zhu HG ... -  《PATHOLOGY INTERNATIONAL》

Upregulation of DNMT1 mediated by HBx suppresses RASSF1A expression independent of DNA methylation.

Qiu X ，Zhang L ，Lu S ，Song Y ，Lao Y ，Hu J ，Fan H ... -  《-》