title: Induction of cyclooxygenase-2 expression by hepatitis B virus depends on demethylation-associated recruitment of transcription factors to the promoter.
abstract: BACKGROUND
  The hepatitis B virus (HBV) is a major etiological factor of inflammation and damage to the liver resulting in hepatocellular carcinoma. Transcription factors play important roles in the disordered gene expression and liver injury caused by HBV. However, the molecular mechanisms behind this observation have not been defined.
  
  
  RESULTS
  In this study, we observed that circulating prostaglandin (PGE) 2 synthesis was increased in patients with chronic hepatitis B infection, and detected elevated cyclooxygenase (COX)-2 expression in HBV- and HBx-expressing liver cells. Likewise, the association of HBx with C/EBPβ contributed to the induction of COX-2. The COX-2 promoter was hypomethylated in HBV-positive cells, and specific demethylation of CpG dinucleotides within each of the two NF-AT sites in the COX-2 promoter resulted in the increased binding affinity of NF-AT to the cognate sites in the promoter, followed by increased COX-2 expression and PGE2 accumulation. The DNA methylatransferase DNMT3B played a key role in the methylation of the COX-2 promoter, and its decreased binding to the promoter was responsible for the regional demethylation of CpG sites, and for the increased binding of transcription factors in HBV-positive cells.
  
  
  CONCLUSIONS
  Our results indicate that upregulation of COX-2 by HBV and HBx is mediated by both demethylation events and recruitment of multiple transcription factors binding to the promoter.
authors.affiliation: State Key Laboratory of Virology and College of Life Sciences, Chinese-French Liver Disease Research Institute of Wuhan University (Zhongnan Hospital), Wuhan University, Wuhan 430072, PR China.
authors.forename: Xin
authors.initials: X
authors.lastname: Yue
authors.forename: Fang
authors.initials: F
authors.lastname: Yang
authors.forename: Yongbo
authors.initials: Y
authors.lastname: Yang
authors.forename: Yongxin
authors.initials: Y
authors.lastname: Mu
authors.forename: Wei
authors.initials: W
authors.lastname: Sun
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Dongping
authors.initials: D
authors.lastname: Xu
authors.forename: Jianguo
authors.initials: J
authors.lastname: Wu
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhu
mesh_terms: D000328:Adult; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006515:Hepatitis B virus / Q000235:genetics / Q000378:metabolism*; D019694:Hepatitis B, Chronic / Q000201:enzymology* / Q000235:genetics* / Q000378:metabolism / Q000821:virology; D006801:Humans; D008297:Male; D008745:Methylation; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D054334:Viral Regulatory and Accessory Proteins
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; D015534:Trans-Activators; D014157:Transcription Factors; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; D051546:Cyclooxygenase 2