Oncotarget

Research Papers:

Extrachromosomal HPV-16 LCR transcriptional activation by HDACi opposed by cellular differentiation and DNA integration

Ekaterina Dimitrova Bojilova, Christine Weyn, Marie-Hélène Antoine and Véronique Fontaine _

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Oncotarget. 2016; 7:75526-75538. https://doi.org/10.18632/oncotarget.12263

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Abstract

Ekaterina Dimitrova Bojilova1, Christine Weyn1, Marie-Hélène Antoine2, Véronique Fontaine1

1Université Libre de Bruxelles (ULB), Faculty of Pharmacy, Unit of Pharmaceutical Microbiology and Hygiene, 1050 Brussels, Belgium

2Université Libre de Bruxelles (ULB) Faculty of Medicine, Laboratory of Experimental Hormonology, 1070 Brussels, Belgium

Correspondence to:

Véronique Fontaine, email: vfontain@ulb.ac.be

Keywords: human papillomavirus, histone deacetylase inhibitor, transcription, integration, differentiation

Received: April 07, 2016    Accepted: September 13, 2016    Published: September 26, 2016

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.


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