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Impact of Histone Deacetylase Inhibitors on the HPV-16 Transcriptional Activity and Genomic Integration

par Bojilova Dimitrova, Ekaterina
Président du jury Jijakli, Hassan
Promoteur Fontaine, Véronique
Publication Non publié, 2019-04-30

Thèse de doctorat

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Résumé :

SUMMARYHuman papillomaviruses (HPV) are small, non-enveloped viruses with a dsDNA genome. About 40 HPV types infect the mucosa and skin of the anogenital tract, and they are further subdivided into low-risk HPV (LR-HPV) and high-risk HPV (HR-HPV). Long-term, persistent infections with the latter type could result in the development of cervical cancer. Cervical cancer is the second most prevalent cancer worldwide, and the third leading cause of cancer-related deaths in women. HR-HPV DNA is frequently found integrated in cervical carcinoma tissue. Thus, HR-HPV integration is considered to be mechanistically linked to virus-promoted malignancy. Several complex and sometimes inter-linked signal transduction pathways, collectively termed as the DNA Damage Response (DDR), act to sense damage incurred to DNA and ultimately promote its repair. The central players of the DDR are three proteins of the phosphatidylinositol 3-kinase-like protein kinase (PIKK) family, ataxia telangiectasia mutated (ATM), ataxia telangiectasia and Rad3-related (ATR) and DNA protein kinase catalytic subunit (DNA-PKcs). Also crucial to the DDR are members of the poly(ADP)ribose polymerase family (PARP). Interactions between histones modified by PARP enzymes, the PARP enzymes themselves and the X-ray repair cross-complementing protein (XRCC-1), are important for efficient DNA repair. Reversible acetylation of histones plays a key role in the regulation of gene expression and in the DDR. The acetylation of histones, as well as that of numerous other cellular proteins, is carried out by histone acetyl transferases (HAT). This enzymatic process exists in a tightly-regulated equilibrium with lysine deacetylation, which is catalyzed by histone deacetylases (HDAC). HDAC modulate the expression and/or function of key proteins implicated in cancer. In addition, many HDAC are overexpressed in most cancers. Various small-molecule inhibitors of HDAC have been developed. HDAC inhibitors (HDACi) have been shown to promote cancer cell cycle arrest, differentiation and apoptosis. In addition, HDACi are well-documented for their synergistic or additive effects on DNA-damaging agents used in cancer therapy. In spite of a growing body of research however, the cellular and molecular mechanisms behind this phenomenon have not yet been fully uncovered. We evaluated the impact of several pan-HDACi and HDACi analogues on the extrachromosomal and genomically-integrated HPV-16 LCR-driven transcription in various cell lines. Using a classical reporter construct strategy, we report that the pan-HDACi Trichostatin A (TSA), valproate (VPA) and sodium butyrate (NaB) are potent inducers of transcription from the HPV-16 long control region (LCR) in its extrachromosomal form. This effect of HDACi was at least in part mediated by three binding sites of members of the AP-1 family of transcription factors within the viral LCR. HDACi analogues 1 through 6 did not modulate extrachromosomal HPV-16 LCR transcription in a statistically-significant way.