Inhibitors of histone deacetylase arrest cell cycle and induce apoptosis in cervical carcinoma cells circumventing human papillomavirus oncogene expression.
Histone deacetylase (HDAC) inhibitors sodium butyrate and trichostatin A arrest human papillomavirus (HPV)-positive carcinoma cells in G1 to S transition of the cell cycle, which is paralleled by an up-regulation of the cyclin-dependent kinase inhibitors (CKIs) p21CIP1 and p27KIP1 as well as the complete loss of cdk2 activity. Although HPV expression was hitherto thought to be required to maintain a proliferative phenotype of these cells, cdk2 suppression is achieved even in the presence of ongoing viral transcription. While CKIs normally cannot exert their cdk2-inhibitory function in the presence of the viral oncoprotein E7, co-immunoprecipitation experiments revealed that E7 binding is prevented. Increase of p27KIP1 correlates with down-regulation of p45SKP2, a component of the ubiquitin-protein ligase SCF(SKP2) controlling the half-life of regulatory proteins during the cell cycle. HDAC inhibition also triggered an E7-dependent degradation of pRb, while the levels of E2F remained unaffected. The presence of free intracellular E2F and the concomitant up-regulation of CKIs during G1 arrest results in a 'conflicting growth situation', which finally renders the cells to undergo apoptosis. These data provide novel molecular insights into how the transforming potential of HPV can be bypassed and open new therapeutical perspectives for the treatment of cervical cancer.
Finzer
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P
Deutsches Krebsforschungszentrum, Forschungsschwerpunkt Angewandte Tumorvirologie, Abteilung Tumorvirus-Immunologie, Im Neuenheimer Feld 242, 69120 Heidelberg, Germany.
Kuntzen
C
C
Soto
U
U
zur Hausen
H
H
Rösl
F
F
D017209:Apoptosis / Q000187:drug effects*; D042846:CDC2-CDC28 Kinases; D002453:Cell Cycle / Q000187:drug effects; D002471:Cell Transformation, Neoplastic; D051357:Cyclin-Dependent Kinase 2; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D016213:Cyclins / Q000032:analysis / Q000502:physiology; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006367:HeLa Cells; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D008840:Microfilament Proteins / Q000502:physiology; D009124:Muscle Proteins; D009856:Oncogene Proteins, Viral / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D016160:Retinoblastoma Protein / Q000378:metabolism; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000821:virology
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; C052633:E7 protein, Human papillomavirus type 18; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D008840:Microfilament Proteins; D009124:Muscle Proteins; D009856:Oncogene Proteins, Viral; D016160:Retinoblastoma Protein; C058992:Tagln protein, mouse; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases