Back to Search
Start Over
Vorinostat, a pan-HDAC inhibitor, abrogates productive HPV-18 DNA amplification
- Source :
- Proceedings of the National Academy of Sciences. 115
- Publication Year :
- 2018
- Publisher :
- Proceedings of the National Academy of Sciences, 2018.
-
Abstract
- Human papillomaviruses (HPVs) cause epithelial proliferative diseases. Persistent infection of the mucosal epithelia by the high-risk genotypes can progress to high-grade dysplasia and cancers. Viral transcription and protein activities are intimately linked to regulation by histone acetyltransferases and histone deacetylases (HDACs) that remodel chromatin and regulate gene expression. HDACs are also essential to remodel and repair replicating chromatin to enable the progression of replication forks. As such, Vorinostat (suberoylanilide hydroximic acid), and other pan-HDAC inhibitors, are used to treat lymphomas. Here, we investigated the effects of Vorinostat on productive infection of the high-risk HPV-18 in organotypic cultures of primary human keratinocytes. HPV DNA amplifies in the postmitotic, differentiated cells of squamous epithelia, in which the viral oncoproteins E7 and E6 establish a permissive milieu by destabilizing major tumor suppressors, the pRB family proteins and p53, respectively. We showed that Vorinostat significantly reduced these E6 and E7 activities, abrogated viral DNA amplification, and inhibited host DNA replication. The E7-induced DNA damage response, which is critical for both events, was also compromised. Consequently, Vorinostat exposure led to DNA damage and triggered apoptosis in HPV-infected, differentiated cells, whereas uninfected tissues were spared. Apoptosis was attributed to highly elevated proapoptotic Bim isoforms that are known to be repressed by EZH2 in a repressor complex containing HDACs. Two other HDAC inhibitors, Belinostat and Panobinostat, also inhibited viral DNA amplification and cause apoptosis. We suggest that HDAC inhibitors are promising therapeutic agents to treat benign HPV infections, abrogate progeny virus production, and hence interrupt transmission.
- Subjects :
- DNA Replication
Keratinocytes
0301 basic medicine
DNA Repair
DNA damage
Cellular differentiation
Apoptosis
Hydroxamic Acids
Histones
03 medical and health sciences
chemistry.chemical_compound
Panobinostat
medicine
Humans
Vorinostat
Cells, Cultured
Sulfonamides
Mucous Membrane
Multidisciplinary
Bcl-2-Like Protein 11
Human papillomavirus 18
biology
Papillomavirus Infections
EZH2
DNA replication
Oncogene Proteins, Viral
Chromatin
DNA-Binding Proteins
Histone Deacetylase Inhibitors
030104 developmental biology
Histone
PNAS Plus
chemistry
DNA, Viral
biology.protein
Cancer research
Tumor Suppressor Protein p53
medicine.drug
Subjects
Details
- ISSN :
- 10916490 and 00278424
- Volume :
- 115
- Database :
- OpenAIRE
- Journal :
- Proceedings of the National Academy of Sciences
- Accession number :
- edsair.doi.dedup.....be7beb789ac8bd7bb95621d34e0ca587