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.
Highlights
More than 120 human papillomaviruses (HPV) have been described and shown to be globally distributed
We investigated the capacity of the Histone deacetylase inhibitors (HDACi) Valproate (VPA), sodium butyrate (NaBut) and Trichostatin A (TSA) to modulate induction of the luciferase reporter gene expression under the control of the HPV type 16 (HPV-16) Long Control Region (LCR)
In an effort to study these issues in more detail, we first evaluated the impact of several HDACi on the HPV-16 LCR-driven transcription in various cell lines
Summary
More than 120 human papillomaviruses (HPV) have been described and shown to be globally distributed. They seem to coexist with their host over a long period, sometimes in a latent life cycle, as suggested by the wide variety of different types detected at random sites of healthy skin [1, 2]. Mirkovic et al suggest that these cells, when infected by HR HPV, might comprise a nidus for early lesion development [5]. Integration of the viral genome into the host DNA can take place, especially in case of long-term maintenance in the basal epithelium [3]
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