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HDAC inhibitors trigger apoptosis in HPV-positive cells by inducing the E2F-p73 pathway

Patrick Finzer1, Andreas Krueger, Michael Stöhr

  • 1Deutsches Krebsforschungszentrum, Forschungsschwerpunkt Angewandte Tumorvirologie, Abteilung Virale Transformationsmechanismen, Im Neuenheimer Feld 242, 69120 Heidelberg, Germany. p.finzer@dkfz.de

Oncogene
|April 13, 2004
PubMed

Insights

Histone deacetylase (HDAC) inhibitors trigger apoptosis in human papillomavirus (HPV)-positive cells by disrupting mitochondrial potential. This occurs independently of the p53 pathway, offering new therapeutic strategies.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Oncology

Background:

  • Human papillomavirus (HPV) oncoproteins E6 and E7 are crucial for viral oncogenesis.
  • Histone deacetylase (HDAC) inhibitors are investigated as anti-cancer agents.
  • The role of p53 in HPV-induced cancers is complex due to viral protein interference.

Purpose of the Study:

  • To investigate the mechanism by which HDAC inhibitors induce apoptosis in HPV-positive cells.
  • To determine if apoptosis induction relies on the p53 pathway.
  • To explore therapeutic strategies for HPV-positive cancers.

Main Methods:

  • Treatment of HPV-positive cells with HDAC inhibitors.
  • Assessment of mitochondrial transmembrane potential (deltapsim).
  • Analysis of pocket proteins (pRb, p107, p130) and E2F-1.
  • siRNA-mediated knockdown of p53.
  • Evaluation of p73 isoforms.

Main Results:

  • HDAC inhibitors induced apoptosis by disrupting deltapsim in HPV-positive cells, particularly E7-expressing cells.
  • HDAC inhibition caused degradation of pRb, p107, and p130, releasing E2F-1.
  • Proteasomal inhibition rescued pRb and restored cell cycle control.
  • E2F-1 induced apoptosis via p73 isoforms, independent of p53.

Conclusions:

  • HDAC inhibitors induce apoptosis in HPV-positive cells through a p53-independent mechanism.
  • The disruption of mitochondrial potential and pRb degradation are key events.
  • Targeting HDACs offers a potential therapeutic strategy for HPV-positive cancers, bypassing the need for p53 reactivation.

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