title: Extrachromosomal HPV-16 LCR transcriptional activation by HDACi opposed by cellular differentiation and DNA integration.
abstract: Histone deacetylase inhibitors (HDACi) have been shown to render HPV-carrying cells susceptible to intrinsic and extrinsic apoptotic signals. As such, these epigenetic drugs have entered clinical trials in the effort to treat cervical cancer. Here, we studied the effect of common HDACi, with an emphasis on Trichostatin A (TSA), on the transcriptional activity of the HPV-16 Long Control Region (LCR) in order to better understand the impact of these agents in the context of the HPV life cycle and infection. HDACi strongly induced transcription of the firefly luciferase reporter gene under the control of the HPV-16 LCR in a variety of cell lines. In the HaCaT keratinocyte cell line undergoing differentiation induced by TSA, we observed a reduction in LCR-controlled transcription. Three major AP-1 binding sites in the HPV-16 LCR are involved in the regulation by TSA. However, whatever the status of differentiation of the HaCaT cells, TSA induced integration of extra-chromosomal transfected DNA into the cellular genome. Although these data suggest caution using HDACi in the treatment of HR HPV infection, further in vivo studies are necessary to better assess the risk.
authors.affiliation: Université Libre de Bruxelles (ULB), Faculty of Pharmacy, Unit of Pharmaceutical Microbiology and Hygiene, 1050 Brussels, Belgium.
authors.forename: Ekaterina Dimitrova
authors.initials: ED
authors.lastname: Bojilova
authors.affiliation: Université Libre de Bruxelles (ULB), Faculty of Pharmacy, Unit of Pharmaceutical Microbiology and Hygiene, 1050 Brussels, Belgium.
authors.forename: Christine
authors.initials: C
authors.lastname: Weyn
authors.affiliation: Université Libre de Bruxelles (ULB) Faculty of Medicine, Laboratory of Experimental Hormonology, 1070 Brussels, Belgium.
authors.forename: Marie-Hélène
authors.initials: MH
authors.lastname: Antoine
authors.affiliation: Université Libre de Bruxelles (ULB), Faculty of Pharmacy, Unit of Pharmaceutical Microbiology and Hygiene, 1050 Brussels, Belgium.
authors.forename: Véronique
authors.initials: V
authors.lastname: Fontaine
mesh_terms: D001665:Binding Sites; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D015870:Gene Expression; D015967:Gene Expression Regulation, Viral / Q000187:drug effects*; D017930:Genes, Reporter; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D052162:Human papillomavirus 16 / Q000502:physiology*; D006801:Humans; D030361:Papillomavirus Infections / Q000473:pathology / Q000821:virology*; D011485:Protein Binding; D018808:Transcription Factor AP-1 / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects*; D016662:Virus Integration
chemical_list: D056572:Histone Deacetylase Inhibitors; D018808:Transcription Factor AP-1
keywords: differentiation; histone deacetylase inhibitor; human papillomavirus; integration; transcription