Up-regulation of Foxo4 mediated by hepatitis B virus X protein confers resistance to oxidative stress-induced cell death

Ratakorn Srisuttee, Sang Seok Koh, Eun Hee Park, Il Rae Cho, Hye Jin Min, Byung Hak Jhun, Dae Yeul Yu, Sun Park, Do Yun Park, Mo Ock Lee, Diego H. Castrillon, Randal N. Johnston, Young Hwa Chung

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

The hepatitis B virus X (HBX) protein, a regulatory protein of the hepatitis B virus (HBV), has been shown to generate reactive oxygen species (ROS) in human liver cell lines; however, the mechanism by which cells protect themselves under this oxidative stress is poorly understood. Here, we show that HBX induces the up-regulation of Forkhead box class O 4 (Foxo4) not only in Chang cells stably expressing HBX (Chang-HBX) but also in primary hepatic tissues from HBX-transgenic mice. HBX also increased ROS, but reduction of the abundance of ROS using N-acetylcystein (NAC) diminished the levels of Foxo4. Elevated Foxo4 was also detected in nuclei of Chang-HBX cells but not in Chang cells stably expressing the vector (Chang-Vec), suggesting that HBX activates the transcriptional activity of Foxo4. When we examined whether HBX bypasses JNK signaling that targets Foxo4, we found that the activity of JNK but not of ERK is required for the up-regulation of Foxo4 even in the presence of HBX. Furthermore, the reduction of Foxo4 levels using siRNA or a JNK inhibitor rendered Chang-HBX cells sensitive to apoptosis under oxidative stress, suggesting that up-regulation of Foxo4 mediated by HBX enhances resistances to oxidative stress-induced cell death. Accordingly, we propose that Foxo4 may be a useful target for suppression in the treatment of HBV-associated hepatocellular carcinoma cells.

Original languageEnglish (US)
Pages (from-to)255-260
Number of pages6
JournalInternational journal of molecular medicine
Volume28
Issue number2
DOIs
StatePublished - Aug 1 2011

Keywords

  • Forkhead box class O 4
  • Hepatitis B virus X
  • JNK
  • Oxidative stress
  • Reactive oxygen species

ASJC Scopus subject areas

  • Genetics

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  • Cite this

    Srisuttee, R., Koh, S. S., Park, E. H., Cho, I. R., Min, H. J., Jhun, B. H., Yu, D. Y., Park, S., Park, D. Y., Lee, M. O., Castrillon, D. H., Johnston, R. N., & Chung, Y. H. (2011). Up-regulation of Foxo4 mediated by hepatitis B virus X protein confers resistance to oxidative stress-induced cell death. International journal of molecular medicine, 28(2), 255-260. https://doi.org/10.3892/ijmm.2011.699