Hepatitis B virus X protein induces the expression of MTA1 and HDAC1, which enhances hypoxia signaling in hepatocellular carcinoma cells

• Published in: Oncogene Vol. 27; no. 24; pp. 3405 - 3413
• Main Authors: YOO, Y.-G, NA, T.-Y, SEO, H.-W, SEONG, J. K, PARK, C. K, SHIN, Y. K, LEE, M-O
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 29.05.2008; Nature Publishing Group
• Subjects: Acetylation; Angiogenesis; Animals; Biological and medical sciences; Blotting, Western; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Carcinoma, Hepatocellular - virology; Care and treatment; Cell Hypoxia; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cellular biology; Cellular signal transduction; Deacetylation; Fundamental and applied biological sciences. Psychology; Gastroenterology. Liver. Pancreas. Abdomen; Gene Expression; Genetic aspects; Genetics; Hepatitis; Hepatitis B; Hepatitis B virus; Hepatocellular carcinoma; Hepatoma; Histone deacetylase; Histone Deacetylase 1; Histone Deacetylase 2; Histone Deacetylases - genetics; Histone Deacetylases - metabolism; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Hypoxia-inducible factor 1a; Immunoenzyme Techniques; Immunoprecipitation; Liver - metabolism; Liver cancer; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Liver Neoplasms - virology; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Medical sciences; Metastases; Metastasis; Mice; Mice, Inbred C57BL; Mice, Transgenic; Molecular and cellular biology; Oncology; Physiological aspects; Proteasomes; Proteins; Repressor Proteins - genetics; Repressor Proteins - metabolism; Retrospective Studies; Ribonucleic acid; Risk factors; RNA; Signal Transduction; siRNA; Trans-Activators - physiology; Transcription; Transcription Factors - genetics; Transcription Factors - metabolism; Transgenic mice; Tumor Cells, Cultured; Tumor suppressor genes; Tumors; Viral proteins; Viral Regulatory and Accessory Proteins; Viruses; South Korea; Histone deacetylase; Oxygen; Orthohepadnavirus; Hepatic disease; Hepatocellular carcinoma; Malignant tumor; Metastasis; Gene expression; Carcinogenesis; Protein; metastasis-associated protein; Virus; hypoxia-inducible factor-1α; Hepadnaviridae; Digestive diseases; Hypoxia; Hepatitis B virus; Cancer; HBx
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1211000

Expression level of metastasis-associated protein 1 (MTA1) is closely related to tumor growth and metastasis in various cancers. Although increased expression level of MTA1 was observed in hepatocellular carcinoma (HCC), role of MTA1 complex containing histone deacetylase (HDAC) in hepatitis B virus (HBV)-associated hepatocarcinogenesis has not been studied. Here, we demonstrated that HBx strongly induced the expression of MTA1 and HDAC1 genes at transcription level. MTA1 and HDAC1/2 physically associated with hypoxia-inducible factor-1 alpha (HIF-1 alpha) in vivo in the presence of HBx, which was abolished by knockdown of MTA1 by short interfering RNA (siRNA). HBx induced deacetylation of the oxygen-dependent degradation domain of HIF-1 alpha, which was accompanied with dissociation of prolyl hydroxylases and von Hippel-Lindau tumor suppressor from HIF-1 alpha. These results indicate that HBx-induced deacetylation is important for proteasomal degradation of HIF-1 alpha. Further, we observed that protein levels of MTA1 and HDAC1 were increased in the liver of HBx-transgenic mice. Also, there was a higher expression of HDAC1 in HCC than in the adjacent non-tumorous cirrhotic nodules in 10 out of 12 human HBV-associated HCC specimens. Together, our data indicate a positive cross talk between HBx and the MTA1/HDAC complex in stabilizing HIF-1 alpha, which may play a critical role in angiogenesis and metastasis of HBV-associated HCC.