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PLoS Pathog. 2017 Mar 2;13(3):e1006262. doi: 10.1371/journal.ppat.1006262. eCollection 2017 Mar.

Autophagy regulates UBC9 levels during viral-mediated tumorigenesis.

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European Institute of Oncology, Department of Experimental Oncology, Milan, Italy.
European Institute of Oncology, Department of Pathology, Milan, Italy.
Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, Milan, Italy.
Department of Experimental Medicine, University of Genova, Genova, Italy.
Infections and Cancer Biology Group, International Agency for Research on Cancer, Lyon, France.
European Institute of Oncology, Division of Otolaryngology and Head and Neck Surgery, Milan, Italy.
European Institute of Oncology Senology Division, Milan, Italy.
European Institute of Oncology, Plastic Surgery Department, Milan, Italy.
Division of Molecular Diagnostics of Oncogenic Infections, Research Program Infection, Inflammation and Cancer, German Cancer Research Center, Heidelberg, Germany.


UBC9, the sole E2-conjugating enzyme required for SUMOylation, is a key regulator of essential cellular functions and, as such, is frequently altered in cancers. Along these lines, we recently reported that its expression gradually increases during early stages of human papillomavirus (HPV)-mediated cervical lesions transformation. However, a better understanding of how UBC9 is exploited by transforming viral oncoproteins is still needed. In the present study, we show that in human samples HPV drives UBC9 up-regulation also in very early steps of head and neck tumorigenesis, pointing to the important role for UBC9 in the HPV-mediated carcinogenic program. Moreover, using HPV-infected pre-cancerous tissues and primary human keratinocytes as the natural host of the virus, we investigate the pathological meaning and the cellular mechanisms responsible for UBC9 de-regulation in an oncoviral context. Our results show that UBC9 overexpression is promoted by transforming viral proteins to increase host cells' resistance to apoptosis. In addition, ultrastuctural, pharmacological and genetic approaches crucially unveil that UBC9 is physiologically targeted by autophagy in human cells. However, the presence of HPV E6/E7 oncoproteins negatively impacts the autophagic process through selective inhibition of autophagosome-lysosome fusion, finally leading to p53 dependent UBC9 accumulation during viral-induced cellular transformation. Therefore, our study elucidates how UBC9 is manipulated by HPV oncoproteins, details the physiological mechanism by which UBC9 is degraded in cells, and identifies how HPV E6/E7 impact on autophagy. These findings point to UBC9 and autophagy as novel hallmarks of HPV oncogenesis, and open innovative avenues towards the treatment of HPV-related malignancies.

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