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

Oncogene. 2004 Jun 17;23(28):4807-17. doi: 10.1038/sj.onc.1207620.

Abstract

Histone deacetylase (HDAC) inhibitors induce an intrinsic type of apoptosis in human papillomavirus (HPV)-positive cells by disrupting the mitochondrial transmembrane potential (deltapsim). Loss of deltapsim was only detected in E7, but not in E6 oncogene-expressing cells. HDAC inhibition led to a time-dependent degradation of the pocket proteins pRb, p107 and p130, releasing 'free' E2F-1 following initial G1 arrest. Inhibition of proteasomal proteolysis, but not of caspase activity rescued pRb from degradation and functionally restored its inhibitory effect on the cyclin E gene, known to be suppressed by pRb-E2F-1 in conjunction with HDAC1. Using siRNA targeted against p53, E2F-1 still triggered apoptosis by inducing the E2F-responsive proapoptotic alpha- and beta-isoforms of p73. These data may determine future therapeutic strategies in which HDAC inhibitors can effectively eliminate HPV-positive cells by an apoptotic route that does not rely on the reactivation of the 'classical' p53 pathway through a preceding shut-off of viral gene expression.

MeSH terms

  • Apoptosis / drug effects*
  • Base Sequence
  • Cell Cycle Proteins*
  • DNA Primers
  • DNA-Binding Proteins / drug effects
  • DNA-Binding Proteins / physiology*
  • E2F Transcription Factors
  • E2F1 Transcription Factor
  • Enzyme Inhibitors / pharmacology*
  • Genes, Tumor Suppressor
  • HeLa Cells
  • Histone Deacetylase Inhibitors*
  • Humans
  • Intracellular Membranes / drug effects
  • Membrane Potentials / drug effects
  • Membrane Potentials / physiology
  • Mitochondria / drug effects
  • Mitochondria / physiology
  • Nuclear Proteins / drug effects
  • Nuclear Proteins / physiology*
  • Papillomaviridae / pathogenicity*
  • Protein Isoforms / drug effects
  • Protein Isoforms / physiology
  • RNA, Small Interfering / genetics
  • Receptors, Fc / antagonists & inhibitors
  • Transcription Factors / drug effects
  • Transcription Factors / physiology*
  • Tumor Protein p73
  • Tumor Suppressor Proteins

Substances

  • Cell Cycle Proteins
  • DNA Primers
  • DNA-Binding Proteins
  • E2F Transcription Factors
  • E2F1 Transcription Factor
  • E2F1 protein, human
  • Enzyme Inhibitors
  • Histone Deacetylase Inhibitors
  • Nuclear Proteins
  • Protein Isoforms
  • RNA, Small Interfering
  • Receptors, Fc
  • TP73 protein, human
  • Transcription Factors
  • Tumor Protein p73
  • Tumor Suppressor Proteins