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

• Verfasst von: Finzer, Patrick [VerfasserIn]
• Verfasst von: Krammer, Peter H. [VerfasserIn]
• Verfasst von: Rösl, Frank [VerfasserIn]
• Titel: HDAC inhibitors trigger apoptosis in HPV-positive cells by inducing the E2F-p73 pathway
• Verf.angabe: Patrick Finzer, Andreas Krueger, Michael Stöhr, Dirk Brenner, Ubaldo Soto, Christian Kuntzen, Peter H. Krammer and Frank Rösl
• E-Jahr: 2004
• Jahr: 12 April 2004
• Umfang: 11 S.
• Teil: volume:23
• Teil: year:2004
• Teil: number:28
• Teil: pages:4807-4817
• Teil: extent:11
• Fussnoten: Gesehen am 06.04.2021
• Titel Quelle: Enthalten in: Oncogene
• Ort Quelle: London : Springer Nature, 1997
• Jahr Quelle: 2004
• Band/Heft Quelle: 23(2004), 28, Seite 4807-4817
• ISSN Quelle: 1476-5594
• DOI: doi:10.1038/sj.onc.1207620
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1753148677

Abstract

Histone deacetylase (HDAC) inhibitors induce an intrinsic type of apoptosis in human papillomavirus (HPV)-positive cells by disrupting the mitochondrial transmembrane potential (ΔΨm). Loss of ΔΨm 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 α- and β-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.