Mechanism of HPV E6 oncogene mediated silencing of Syntenin-2 gene expression and role of Syntenin-2 in skin homeostasis.

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Human papillomaviruses (HPV) are associated with the development of epithelial cancers and high-risk HPV of the genus alphapapillomavirus (alphaPV) have been proven to be a necessary causative factor for cervical cancer. HPV types of genus betapapillomavirus (betaPV) have been implicated in the development of cutaneous tumours, especially squamous cell carcinomas (SCC) and actinic keratosis. The E6 proteins from high-risk alphaPV (e.g. HPV16) are characterized by the presence of a PDZ binding motif, through which they interact with a number of cellular PDZ domain-containing substrates and cooperate in their degradation. PDZ proteins play a major role in maintenance of cell polarity, formation of cell-cell adherence junctions, and organization of multiprotein signaling complexes as scaffolding proteins. Their targeting by E6 may cause loss of cell polarity and morphological conversion, associated with epithelial-mesenchymal transition, leading to transformation and carcinogenesis. The ability of these E6 proteins to bind to PDZ domain proteins correlates with the oncogenic potential of the virus. The E6 proteins of oncogenic HPV from betaPV (e.g. HPV8) do not encode a PDZ-binding motif. We recently found, that the PDZ domain protein Syntenin-2 is transcriptionally downregulated in primary human epidermal keratinocytes (PHEK) by HPV8-E6. The mRNA levels of the known HPV16-E6 PDZ protein-targets Dlg, Scribble, Magi-1/-3, PSD95 and Mupp1 were not changed by HPV8-E6. Surprisingly, HPV16-E6 also repressed transcription of Syntenin-2 but with a lesser efficiency than HPV8-E6. These results identified Syntenin-2 as the first PDZ-domain protein being controlled by HPV8 and HPV16 at mRNA level. ShRNA mediated knock-down of Syntenin-2 led to an inhibition of differentiation and an increase in proliferation capacity in PHEK. We therefore hypothesize that a comprehensive evaluation of Syntenin-2 gene expression will define the specific contribution of Syntenin-2 in skin homeostasis and keratinocyte proliferation and immortalization. In addition, understanding of the regulatory mechanisms through which the high-risk HPV types 8 and 16 control Syntenin-2 gene expression may be of critical importance and may provide further aspects for our understanding of HPV pathogenesis in the future.