HDAC inhibitors trigger apoptosis in HPV-positive cells by inducing the E2F-p73 pathway.
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.
Finzer
Patrick
P
Deutsches Krebsforschungszentrum, Forschungsschwerpunkt Angewandte Tumorvirologie, Abteilung Virale Transformationsmechanismen, Im Neuenheimer Feld 242, 69120 Heidelberg, Germany. p.finzer@dkfz.de
Krueger
Andreas
A
Stöhr
Michael
M
Brenner
Dirk
D
Soto
Ubaldo
U
Kuntzen
Christian
C
Krammer
Peter H
PH
Rösl
Frank
F
D017209:Apoptosis / Q000187:drug effects*; D001483:Base Sequence; D018797:Cell Cycle Proteins; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000502:physiology*; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D016147:Genes, Tumor Suppressor; D006367:HeLa Cells; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D007425:Intracellular Membranes / Q000187:drug effects; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D009687:Nuclear Proteins / Q000187:drug effects / Q000502:physiology*; D027383:Papillomaviridae / Q000472:pathogenicity*; D020033:Protein Isoforms / Q000187:drug effects / Q000502:physiology; D034741:RNA, Small Interfering / Q000235:genetics; D011961:Receptors, Fc / Q000037:antagonists & inhibitors; D014157:Transcription Factors / Q000187:drug effects / Q000502:physiology*; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins
D018797:Cell Cycle Proteins; D017931:DNA Primers; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D009687:Nuclear Proteins; D020033:Protein Isoforms; D034741:RNA, Small Interfering; D011961:Receptors, Fc; C000606460:TP73 protein, human; D014157:Transcription Factors; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins