Retinoic acid receptor beta silences human papillomavirus-18 oncogene expression by induction of de novo methylation and heterochromatinization of the viral control region.
Retinoic acid receptor beta2 (RAR beta2) is often down-regulated during the multistep process to cervical cancer. In that way, its inhibitory function on the transcription factor AP-1, indispensable to maintain human papillomavirus (HPV) gene expression is relieved. Using HPV-18 positive HeLa cells as a model system, we show that ectopic expression of RAR beta2 is able to down-regulate HPV-18 transcription by selectively abrogating the binding of AP-1 to the viral regulatory region in a ligand-independent manner. This resulted in down-regulation of the viral mRNAs at the level of initiation of transcription. Decreased oncogene expression was accompanied by a re-induction of cell cycle inhibitory proteins such as p53, p21(CIP1), and p27(KIP) as well as by a cessation of cellular growth. Reduced transcriptional activity as a consequence of AP-1 reduction by selective c-Jun degradation apparently targets the HPV-18 regulatory region for epigenetic modification such as de novo methylation and nucleosomal condensation. This mechanism is otherwise counterbalanced by active and abundant viral transcription in malignant cells, because RAR beta2 itself becomes inactivated during cervical carcinogenesis. Hence, our study shows that the temporal co-existence of a potential repressor and viral oncoproteins is mutually exclusive and provides evidence of a cross-talk between a nuclear receptor, AP-1, and the epigenetic machinery.
Angewandte Tumorvirologie, Abteilung Virale Transformationsmechanismen, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 242, 69120 Heidelberg, Germany.
Johanna
J
De-Castro Arce
Angewandte Tumorvirologie, Abteilung Virale Transformationsmechanismen, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 242, 69120 Heidelberg, Germany.
Elke
E
Göckel-Krzikalla
Angewandte Tumorvirologie, Abteilung Virale Transformationsmechanismen, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 242, 69120 Heidelberg, Germany. Electronic address: F.Roesl@dkfz.de.
Frank
F
Rösl
D002135:Calcium-Binding Proteins / Q000378:metabolism; D002453:Cell Cycle; D002472:Cell Transformation, Viral; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D019175:DNA Methylation; D004279:DNA, Viral / Q000378:metabolism*; D015536:Down-Regulation; D005260:Female; D015967:Gene Expression Regulation, Viral; D020868:Gene Silencing; D016758:Genes, jun; D006367:HeLa Cells; D006570:Heterochromatin / Q000378:metabolism / Q000821:virology*; D052161:Human papillomavirus 18 / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D009707:Nucleosomes / Q000378:metabolism; D012367:RNA, Viral / Q000096:biosynthesis; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D020218:Response Elements; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D002583:Uterine Cervical Neoplasms / Q000378:metabolism / Q000821:virology*; D014764:Viral Proteins / Q000378:metabolism
C493956:CDKN1A protein, human; C109198:CIB1 protein, human; D002135:Calcium-Binding Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004279:DNA, Viral; D006570:Heterochromatin; D009707:Nucleosomes; D012367:RNA, Viral; D018168:Receptors, Retinoic Acid; D018808:Transcription Factor AP-1; D016159:Tumor Suppressor Protein p53; D014764:Viral Proteins; C082925:retinoic acid receptor beta