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Updated: Mar 14, 2026
Repressing Gene Transcription by Redirecting Cellular Machinery with Chemical Epigenetic Modifiers
Published on: September 20, 2018
Extrachromosomal HPV-16 LCR transcriptional activation by HDACi opposed by cellular differentiation and DNA
Ekaterina Dimitrova Bojilova1, Christine Weyn1, Marie-Hélène Antoine2
1Université Libre de Bruxelles (ULB), Faculty of Pharmacy, Unit of Pharmaceutical Microbiology and Hygiene, 1050 Brussels, Belgium.
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.
Insights
Histone deacetylase inhibitors (HDACi) increase HPV-16 Long Control Region transcription, but caution is advised due to potential DNA integration risks. Further in vivo studies are needed to assess safety in HPV infections.
Area of Science:
- Epigenetics
- Virology
- Molecular Biology
Background:
- Histone deacetylase inhibitors (HDACi) are epigenetic drugs being investigated for cervical cancer treatment.
- HDACi can sensitize human papillomavirus (HPV)-infected cells to apoptosis.
- The impact of HDACi on the HPV life cycle requires further elucidation.
Purpose of the Study:
- To investigate the effect of HDAC inhibitors, particularly Trichostatin A (TSA), on HPV-16 Long Control Region (LCR) transcriptional activity.
- To understand the implications of HDACi on HPV infection and life cycle.
- To assess the role of AP-1 binding sites in TSA-mediated regulation of HPV-16 LCR.
Main Methods:
- Utilized reporter gene assays to measure transcription driven by the HPV-16 LCR.
- Examined the effects of TSA on HaCaT keratinocyte differentiation.
- Investigated the impact of TSA on the integration of extra-chromosomal DNA into the host genome.
Main Results:
- HDAC inhibitors significantly induced transcription from the HPV-16 LCR in various cell lines.
- TSA treatment led to reduced LCR-controlled transcription in differentiating HaCaT cells.
- TSA promoted the integration of transfected DNA into the HaCaT cell genome, irrespective of differentiation status.
- Specific AP-1 binding sites within the HPV-16 LCR were identified as key regulatory elements for TSA's effects.
Conclusions:
- HDAC inhibitors can modulate HPV-16 LCR transcription, with context-dependent effects related to cellular differentiation.
- The observed induction of DNA integration by TSA warrants caution regarding the use of HDACi in treating high-risk HPV infections.
- Further in vivo research is essential to comprehensively evaluate the risks associated with HDACi therapy for HPV-related conditions.
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