Doxorubicin Activates Hepatitis B Virus Replication by Elevation of p21 (Waf1/Cip1) and C/EBPα Expression

PLoS One. 2015 Jun 29;10(6):e0131743. doi: 10.1371/journal.pone.0131743. eCollection 2015.

Abstract

Hepatitis B virus reactivation is an important medical issue in cancer patients who undergo systemic chemotherapy. Up to half of CHB carriers receiving chemotherapy develop hepatitis and among these cases a notable proportion are associated with HBV reactivation. However, the molecular mechanism(s) through which various chemotherapeutic agents induce HBV reactivation is not yet fully understood. In this study, we investigated the role of the cell cycle regulator p21 (Waf1/Cip1) in the modulation of HBV replication when a common chemotherapeutic agent, doxorubicin, is present. We showed that p21 expression was increased by doxorubicin treatment. This elevation in p21 expression enhanced the expression of CCAAT/enhancer-binding protein α (C/EBPα); such an increase is likely to promote the binding of C/EBPα to the HBV promoter, which will contribute to the activation of HBV replication. Our current study thus reveals the mechanism underlying doxorubicin modulation of HBV replication and provides an increased understanding of HBV reactivation in CHB patients who are receiving systemic chemotherapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibiotics, Antineoplastic / pharmacology*
  • CCAAT-Enhancer-Binding Protein-alpha / genetics*
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics*
  • Doxorubicin / pharmacology*
  • Gene Expression
  • Gene Expression Regulation / drug effects
  • Hep G2 Cells
  • Hepatitis B virus / drug effects*
  • Hepatitis B virus / physiology*
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism
  • Humans
  • Promoter Regions, Genetic
  • Protein Binding
  • RNA, Viral
  • Response Elements
  • Virus Activation / drug effects*
  • Virus Replication / drug effects*

Substances

  • Antibiotics, Antineoplastic
  • CCAAT-Enhancer-Binding Protein-alpha
  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • RNA, Viral
  • Doxorubicin

Grants and funding

This research was supported by the National Health Research Institute (NHRI) grant (MG-102-PP-07) and the National Science Council (NSC) grant (NSC 101-2320-B-400-009). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.