Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

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

Oncogene volume 27, pages 3405–3413 (2008)Cite this article

Abstract

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-1α (HIF-1α) 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-1α, which was accompanied with dissociation of prolyl hydroxylases and von Hippel–Lindau tumor suppressor from HIF-1α. These results indicate that HBx-induced deacetylation is important for proteasomal degradation of HIF-1α. 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-1α, which may play a critical role in angiogenesis and metastasis of HBV-associated HCC.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

References

  • Armeanu S, Pathil A, Venturelli S, Mascagni P, Weiss TS, Gottlicher M et al. (2005). Apoptosis on hepatoma cells but not on primary hepatocytes by histone deacetylase inhibitors valproate and ITF2357. J Hepatol 42: 210–217.

    Article  CAS  Google Scholar 

  • Arnesen T, Kong X, Evjenth R, Gromyko D, Varhaug JE, Lin Z et al. (2005). Interaction between HIF-1 alpha (ODD) and hARD1 does not induce acetylation and destabilization of HIF-1 alpha. FEBS Lett 579: 6428–6432.

    Article  CAS  Google Scholar 

  • Bilton R, Mazure N, Trottier E, Hattab M, Dery MA, Richard DE et al. (2005). Arrest-defective-1 protein, an acetyltransferase, does not alter stability of hypoxia-inducible factor (HIF)-1α and is not induced by hypoxia or HIF. J Biol Chem 280: 31132–31140.

    Article  CAS  Google Scholar 

  • Bilton R, Trottier E, Pouyssegur J, Brahimi-Horn MC . (2006). ARDent about acetylation and deacetylation in hypoxia signalling. Trends Cell Biol 16: 616–621.

    Article  CAS  Google Scholar 

  • Brahimi-Horn C, Mazure N, Pouyssegur J . (2005). Signalling via the hypoxia-inducible factor-1alpha requires multiple posttranslational modifications. Cell Signal 17: 1–9.

    Article  CAS  Google Scholar 

  • Caron C, Col E, Khochbin S . (2002). The viral control of cellular acetylation signaling. Bioessays 25: 58–65.

    Article  CAS  Google Scholar 

  • Chan DW, Ng IO . (2006). Knockdown of hepatitis B virus X protein reduces the tumorigenicity of hepatocellular carcinoma cells. J Pathol 208: 372–380.

    Article  CAS  Google Scholar 

  • Chang CC, Lin MT, Lin BR, Jeng YM, Chen ST, Chu CY et al. (2006). Effect of connective tissue growth factor on hypoxia-inducible factor 1alpha degradation and tumor angiogenesis. J Natl Cancer Inst 98: 984–995.

    Article  CAS  Google Scholar 

  • Chung TW, Lee YC, Kim CH . (2004). Hepatitis B viral HBx induces matrix metalloproteinase-9 gene expression through activation of ERK and PI-3K/AKT pathways: involvement of invasive potential. FASEB J 18: 1123–1125.

    Article  CAS  Google Scholar 

  • Cougot D, Neuveut C, Buendia MA . (2005). HBV induced carcinogenesis. J Clin Virol 34 (Suppl 1): S75–S78.

    Article  CAS  Google Scholar 

  • Fath DM, Kong X, Liang D, Lin Z, Chou A, Jiang Y et al. (2006). Histone deacetylase inhibitors repress the transactivation potential of hypoxia-inducible factors independently of direct acetylation of HIF-alpha. J Biol Chem 281: 13612–13619.

    Article  CAS  Google Scholar 

  • Fisher TS, Etages SD, Hayes L, Crimin K, Li B . (2005). Analysis of ARD1 function in hypoxia response using retroviral RNA interference. J Biol Chem 280: 17749–17757.

    Article  CAS  Google Scholar 

  • Frati A, Salvati M, Giarnieri E, Santoro A, Rocchi G, Frati L . (2002). Brain metastasis from hepatocellular carcinoma associated with hepatitis B virus. J Exp Clin Cancer Res 21: 321–327.

    CAS  Google Scholar 

  • Glozak MA, Sengupta N, Zhang X, Seto E . (2005). Acetylation and deacetylation of non-histone proteins. Gene 363: 15–23.

    Article  CAS  Google Scholar 

  • Hamatsu T, Rikimaru T, Yamashita Y, Aishima S, Tanaka S, Shirabe K et al. (2003). The role of MTA1 gene expression in human hepatocellular carcinoma. Oncol Rep 10: 599–604.

    CAS  Google Scholar 

  • Huang GW, Yang LY, Lu WQ . (2005). Expression of hypoxia-inducible factor 1alpha and vascular endothelial growth factor in hepatocellular carcinoma: impact on neovascularization and survival. World J Gastroenterol 11: 1705–1708.

    Article  CAS  Google Scholar 

  • Jeong JW, Bae MK, Ahn MY, Kim SH, Sohn TK, Bae MH et al. (2002). Regulation and destabilization of HIF-1 by ARD1-mediated acetylation. Cell 111: 709–720.

    Article  CAS  Google Scholar 

  • Kim CM, Koike K, Saito I, Miyamura T, Jay G . (1991). HBx gene of hepatitis B virus induces liver cancer in transgenic mice. Nature 351: 317–320.

    Article  CAS  Google Scholar 

  • Kim MS, Kwon HJ, Lee YM, Baek JH, Jang JE, Lee SW et al. (2001). Histone deacetylases induce angiogenesis by negative regulation of tumor suppressor genes. Nat Med 7: 437–443.

    Article  Google Scholar 

  • Kim SH, Jeong JW, Park JA, Lee JW, Seo JH, Jung BK et al. (2007). Regulation of the HIF-1alpha stability by histone deacetylases. Oncol Rep 17: 647–651.

    CAS  Google Scholar 

  • Kondo Y, Wada K . (1991). Intrahepatic metastasis of hepatocellular carcinoma: a histopathologic study. Hum Pathol 22: 125–130.

    Article  CAS  Google Scholar 

  • Kong X, Lin Z, Liang D, Fath D, Sang N, Caro J . (2006). Histone deacetylase inhibitors induce VHL and ubiquitin-independent proteasomal degradation of hypoxia-inducible factor 1alpha. Mol Cell Biol 26: 2019–2028.

    Article  CAS  Google Scholar 

  • Kumar R, Wang RA, Bagheri-Yarmand R . (2003). Emerging roles of MTA family members in human cancers. Semin Oncol 30: 30–37.

    Article  CAS  Google Scholar 

  • Lara-Pezzi E, Gomez-Gaviro MV, Galvez BG, Mira E, Iniguez MA, Fresno M et al. (2002). The hepatitis B virus X protein promotes tumor cell invasion by inducing membrane-type matrix metalloproteinase-1 and cyclooxygenase-2 expression. J Clin Invest 110: 1831–1838.

    Article  CAS  Google Scholar 

  • Lara-Pezzi E, Majano PL, Yanez-Mo M, Gomez-Gonzab M, Carretero M, Moreno-Otero R et al. (2001b). Effect of the hepatitis B virus HBx protein on integrin-mediated adhesion to and migration on extracellular matrix. J Hepatol 34: 409–415.

    Article  CAS  Google Scholar 

  • Lara-Pezzi E, Roche S, Andrisani OM, Sanchez-Madrid F, Lopez-Cabrera M . (2001a). The hepatitis B virus HBx protein induces adherens junction disruption in an src-dependent manner. Oncogene 20: 3323–3331.

    Article  CAS  Google Scholar 

  • Maxwell PH . (2005). The HIF pathway in cancer. Semin Cell Dev Biol 16: 523–530.

    Article  CAS  Google Scholar 

  • Minucci S, Pelicci PG . (2006). Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat Rev Cancer 6: 38–51.

    Article  CAS  Google Scholar 

  • Mishra SK, Mazumdar A, Vadlamudi RK, Li F, Wang RA, Yu W et al. (2003). MICoA, a novel metastasis-associated protein 1 (MTA1) interacting protein coactivator, regulates estrogen receptor-α transactivation functions. J Biol Chem 278: 19209–19219.

    Article  CAS  Google Scholar 

  • Moon EJ, Jeong CH, Jeong JW, Kim KR, Yu DY, Murakami S et al. (2004a). Hepatitis B virus X protein induces angiogenesis by stabilizing hypoxia-inducible factor-1alpha. FASEB J 18: 382–384.

    Article  CAS  Google Scholar 

  • Moon WS, Chang K, Tarnawski AS . (2004b). Overexpression of metastatic tumor antigen 1 in hepatocellular carcinoma: relationship to vascular invasion and estrogen receptor-alpha. Hum Pathol 35: 424–429.

    Article  CAS  Google Scholar 

  • Murakami S . (2001). Hepatitis B virus X protein: a multifunctional viral regulator. J Gastroenterol 36: 651–660.

    Article  CAS  Google Scholar 

  • Murray-Rust TA, Oldham NJ, Hewitson KS, Schofield CJ . (2006). Purified recombinant hARD1 does not catalyse acetylation of Lys532 of HIF-1alpha fragments in vitro. FEBS Lett 580: 1911–1918.

    Article  CAS  Google Scholar 

  • Nicolson GL, Nawa A, Toh Y, Taniguchi S, Nishimori K, Moustafa A . (2003). Tumor metastasis-associated human MTA1 gene and its MTA1 protein product: role in epithelial cancer cell invasion, proliferation and nuclear regulation. Clin Exp Metastasis 20: 19–24.

    Article  CAS  Google Scholar 

  • Ou DP, Tao YM, Chang ZG, Tang FQ, Yang LY . (2006). Hepatocellular carcinoma cells containing hepatitis B virus X protein have enhanced invasive potential conditionally. Dig Liver Dis 38: 262–267.

    Article  CAS  Google Scholar 

  • Pathil A, Armeanu S, Venturelli S, Mascagni P, Weiss TS, Gregor M et al. (2006). HDAC inhibitor treatment of hepatoma cells induces both TRAIL-independent apoptosis and restoration of sensitivity to TRAIL. Hepatol 43: 425–434.

    Article  CAS  Google Scholar 

  • Qian DZ, Kachhap SK, Collis SJ, Verheul HM, Carducci MA, Atadja P et al. (2006). Class II histone deacetylases are associated with VHL-independent regulation of hypoxia-inducible factor 1alpha. Cancer Res 6: 8814–8821.

    Article  Google Scholar 

  • Toh Y, Kuwano H, Mori M, Nicolson GL, Sugimachi K . (1999). Overexpression of metastasis-associated MTA1 mRNA in invasive oesophageal carcinomas. Br J Cancer 79: 1723–1726.

    Article  CAS  Google Scholar 

  • Toh Y, Pencil SD, Nicolson GL . (1994). A novel candidate metastasis-associated gene, mta1, differentially expressed in highly metastatic mammary adenocarcinoma cell lines. cDNA cloning, expression, and protein analyses. J Biol Chem 269: 22958–22963.

    CAS  Google Scholar 

  • Wada H, Nagano H, Yamamoto H, Yang Y, Kondo M, Ota H et al. (2006). Expression pattern of angiogenic factors and prognosis after hepatic resection in hepatocellular carcinoma: importance of angiopoietin-2 and hypoxia-induced factor-1 alpha. Liver Int 26: 414–423.

    Article  CAS  Google Scholar 

  • Wang LH, Kim SH, Lee JH, Choi YL, Kim YC, Park TS et al. (2007). Inactivation of SMAD4 tumor suppressor gene during gastric carcinoma progression. Clin Cancer Res 13: 102–110.

    Article  Google Scholar 

  • Wu BK, Li CC, Chen HJ, Chang JL, Jeng KS, Chou CK et al. (2006). Blocking of G1/S transition and cell death in the regenerating liver of hepatitis B virus X protein transgenic mice. Biochem Biophys Res Commun 340: 916–928.

    Article  CAS  Google Scholar 

  • Yeo MG, Yoo YG, Choi HS, Pak YK, Lee MO . (2005). Negative cross-talk between Nur77 and small heterodimer partner and its role in apoptotic cell death of hepatoma cells. Mol Endocrinol 19: 950–963.

    Article  CAS  Google Scholar 

  • Yoo YG, Cho S, Park S, Lee MO . (2004). The carboxy-terminus of the hepatitis B virus X protein is necessary and sufficient for the activation of hypoxia-inducible factor-1α. FEBS Lett 577: 121–126.

    Article  CAS  Google Scholar 

  • Yoo YG, Kong G, Lee MO . (2006). Metastasis-associated protein 1 enhances stability of hypoxia-inducible factor-1alpha protein by recruiting histone deacetylase 1. EMBO J 25: 1231–1241.

    Article  CAS  Google Scholar 

  • Yoo YG, Oh SH, Park ES, Cho H, Lee N, Park H et al. (2003). Hepatitis B virus X protein enhances transcriptional activity of hypoxia-inducible factor-1α through activation of mitogen-activated protein kinase pathway. J Biol Chem 278: 39076–39084.

    Article  CAS  Google Scholar 

  • Yu DY, Moon HB, Son JK, Jeong S, Yu SL, Yoon H et al. (1999). Incidence of hepatocellular carcinoma in transgenic mice expressing the hepatitis B virus X-protein. J Hepatol 31: 123–132.

    Article  CAS  Google Scholar 

  • Yu FL, Liu HJ, Lee JW, Liao MH, Shih WL . (2005). Hepatitis B virus X protein promotes cell migration by inducing matrix metalloproteinase-3. J Hepatol 42: 520–527.

    Article  CAS  Google Scholar 

  • Yun C, Um HR, Jin YH, Wang JH, Lee MO, Park S et al. (2002). NF-kappaB activation by hepatitis B virus X (HBx) protein shifts the cellular fate toward survival. Cancer Lett 184: 97–104.

    Article  CAS  Google Scholar 

  • Zhang X, Zhang H, Ye L . (2006). Effects of hepatitis B virus X protein on the development of liver cancer. J Lab Clin Med 147: 58–66.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the Korea Science and Engineering Foundation (2006-02634 and R01-2007-000-20306-0) and the Ministry of Education as The Brain Korea 21 Project.

Author information

Authors and Affiliations

  1. College of Pharmacy, Seoul National University, Seoul, Korea

    Y-G Yoo, T-Y Na, H-W Seo, Y K Shin & M-O Lee

  2. Bio-MAX Institute, Seoul National University, Seoul, Korea

    Y-G Yoo, T-Y Na, H-W Seo & M-O Lee

  3. College of Veterinary Medicine, Seoul National University, Seoul, Korea

    J K Seong

  4. Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

    C K Park

Authors
  1. Y-G Yoo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. T-Y Na
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. H-W Seo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J K Seong
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. C K Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Y K Shin
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. M-O Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M-O Lee.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yoo, YG., Na, TY., Seo, HW. et al. Hepatitis B virus X protein induces the expression of MTA1 and HDAC1, which enhances hypoxia signaling in hepatocellular carcinoma cells. Oncogene 27, 3405–3413 (2008). https://doi.org/10.1038/sj.onc.1211000

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1211000

Keywords

This article is cited by

Search

Advanced search

Quick links