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Aberrant epigenetic modifications in hepatocarcinogenesis induced by hepatitis B virus X protein.
Gastroenterology. 2007 Apr; 132(4):1476-94.G

Abstract

BACKGROUND & AIMS

The involvement of the hepatitis B virus X (HBx) protein in epigenetic modifications during hepatocarcinogenesis has not been previously characterized. The aim of the present study was to identify the involvement of HBx in regional hypermethylation and global hypomethylation during the formation of hepatocellular carcinoma (HCC).

METHODS

Liver cell lines were transiently or stably transfected with an HBx-expressing vector. DNA methyltransferase (DNMT) promoter activity changes were examined by luciferase assay and chromatin immunoprecipitation. The methylation status of insulin-like growth factor binding protein-3 was examined by methyl-specific polymerase chain reaction and bisulfite sequencing. Global DNA methylation levels were examined using 5-methylcytosine dot blot and methylation-sensitive Southern blot analysis. HBx-mediated DNA methylation abnormalities were confirmed in patient HCC samples using methyl-specific polymerase chain reaction and 5-methylcytosine dot blot analysis.

RESULTS

HBx expression increased total DNMT activities by up-regulation of DNMT1, DNMT3A1, and DNMT3A2 and selectively promoted regional hypermethylation of specific tumor suppressor genes. HBx specifically repressed insulin-like growth factor-3 expression through de novo methylation via DNMT3A1 and DNMT3A2 and by inhibiting SP1 binding via recruiting methyl CpG binding protein 2 to the newly methylated SP1 binding element. HBx also induced global hypomethylation of satellite 2 repeat sequences by down-regulating DNMT3B. The prevalence of these specific methylation abnormalities by HBx was significantly correlated with HBx expression in HBV-infected HCC patients.

CONCLUSIONS

Targeted deregulation of DNMTs by HBx promotes both specific regional hypermethylation and global hypomethylation. These epigenetic modulations by HBx may suggest a mechanism for epigenetic tumorigenesis during HBV-mediated hepatocarcinogenesis.

Authors+Show Affiliations

Liver Cell Signal Transduction Laboratory, Molecular Cancer Research Center, KRIBB, Daejeon, Korea.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17408664

Citation

Park, In Young, et al. "Aberrant Epigenetic Modifications in Hepatocarcinogenesis Induced By Hepatitis B Virus X Protein." Gastroenterology, vol. 132, no. 4, 2007, pp. 1476-94.
Park IY, Sohn BH, Yu E, et al. Aberrant epigenetic modifications in hepatocarcinogenesis induced by hepatitis B virus X protein. Gastroenterology. 2007;132(4):1476-94.
Park, I. Y., Sohn, B. H., Yu, E., Suh, D. J., Chung, Y. H., Lee, J. H., Surzycki, S. J., & Lee, Y. I. (2007). Aberrant epigenetic modifications in hepatocarcinogenesis induced by hepatitis B virus X protein. Gastroenterology, 132(4), 1476-94.
Park IY, et al. Aberrant Epigenetic Modifications in Hepatocarcinogenesis Induced By Hepatitis B Virus X Protein. Gastroenterology. 2007;132(4):1476-94. PubMed PMID: 17408664.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Aberrant epigenetic modifications in hepatocarcinogenesis induced by hepatitis B virus X protein. AU - Park,In Young, AU - Sohn,Bo Hwa, AU - Yu,Eunsil, AU - Suh,Dong Jin, AU - Chung,Young-Hwa, AU - Lee,Je-Ho, AU - Surzycki,Stefan J, AU - Lee,Young Ik, Y1 - 2007/01/25/ PY - 2006/04/26/received PY - 2006/12/14/accepted PY - 2007/4/6/pubmed PY - 2007/5/18/medline PY - 2007/4/6/entrez SP - 1476 EP - 94 JF - Gastroenterology JO - Gastroenterology VL - 132 IS - 4 N2 - BACKGROUND & AIMS: The involvement of the hepatitis B virus X (HBx) protein in epigenetic modifications during hepatocarcinogenesis has not been previously characterized. The aim of the present study was to identify the involvement of HBx in regional hypermethylation and global hypomethylation during the formation of hepatocellular carcinoma (HCC). METHODS: Liver cell lines were transiently or stably transfected with an HBx-expressing vector. DNA methyltransferase (DNMT) promoter activity changes were examined by luciferase assay and chromatin immunoprecipitation. The methylation status of insulin-like growth factor binding protein-3 was examined by methyl-specific polymerase chain reaction and bisulfite sequencing. Global DNA methylation levels were examined using 5-methylcytosine dot blot and methylation-sensitive Southern blot analysis. HBx-mediated DNA methylation abnormalities were confirmed in patient HCC samples using methyl-specific polymerase chain reaction and 5-methylcytosine dot blot analysis. RESULTS: HBx expression increased total DNMT activities by up-regulation of DNMT1, DNMT3A1, and DNMT3A2 and selectively promoted regional hypermethylation of specific tumor suppressor genes. HBx specifically repressed insulin-like growth factor-3 expression through de novo methylation via DNMT3A1 and DNMT3A2 and by inhibiting SP1 binding via recruiting methyl CpG binding protein 2 to the newly methylated SP1 binding element. HBx also induced global hypomethylation of satellite 2 repeat sequences by down-regulating DNMT3B. The prevalence of these specific methylation abnormalities by HBx was significantly correlated with HBx expression in HBV-infected HCC patients. CONCLUSIONS: Targeted deregulation of DNMTs by HBx promotes both specific regional hypermethylation and global hypomethylation. These epigenetic modulations by HBx may suggest a mechanism for epigenetic tumorigenesis during HBV-mediated hepatocarcinogenesis. SN - 0016-5085 UR - https://www.unboundmedicine.com/medline/citation/17408664/Aberrant_epigenetic_modifications_in_hepatocarcinogenesis_induced_by_hepatitis_B_virus_X_protein_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0016-5085(07)00172-2 DB - PRIME DP - Unbound Medicine ER -