title: Autophagy regulates UBC9 levels during viral-mediated tumorigenesis.
abstract: 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.
authors.affiliation: European Institute of Oncology, Department of Experimental Oncology, Milan, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Mattoscio
authors.affiliation: European Institute of Oncology, Department of Pathology, Milan, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Casadio
authors.affiliation: European Institute of Oncology, Department of Experimental Oncology, Milan, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Miccolo
authors.affiliation: European Institute of Oncology, Department of Pathology, Milan, Italy.
authors.forename: Fausto
authors.initials: F
authors.lastname: Maffini
authors.affiliation: Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Raimondi
authors.affiliation: Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, Milan, Italy.|Department of Experimental Medicine, University of Genova, Genova, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Tacchetti
authors.affiliation: Infections and Cancer Biology Group, International Agency for Research on Cancer, Lyon, France.
authors.forename: Tarik
authors.initials: T
authors.lastname: Gheit
authors.affiliation: European Institute of Oncology, Division of Otolaryngology and Head and Neck Surgery, Milan, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Tagliabue
authors.affiliation: European Institute of Oncology Senology Division, Milan, Italy.
authors.forename: Viviana E
authors.initials: VE
authors.lastname: Galimberti
authors.affiliation: European Institute of Oncology, Plastic Surgery Department, Milan, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: De Lorenzi
authors.affiliation: Division of Molecular Diagnostics of Oncogenic Infections, Research Program Infection, Inflammation and Cancer, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Michael
authors.identifier: 0000-0002-4720-8306
authors.initials: M
authors.lastname: Pawlita
authors.affiliation: European Institute of Oncology, Division of Otolaryngology and Head and Neck Surgery, Milan, Italy.
authors.forename: Fausto
authors.initials: F
authors.lastname: Chiesa
authors.affiliation: European Institute of Oncology, Division of Otolaryngology and Head and Neck Surgery, Milan, Italy.
authors.forename: Mohssen
authors.initials: M
authors.lastname: Ansarin
authors.affiliation: Infections and Cancer Biology Group, International Agency for Research on Cancer, Lyon, France.
authors.forename: Massimo
authors.initials: M
authors.lastname: Tommasino
authors.affiliation: European Institute of Oncology, Department of Experimental Oncology, Milan, Italy.
authors.forename: Susanna
authors.identifier: 0000-0002-9721-0850
authors.initials: S
authors.lastname: Chiocca
mesh_terms: D017209:Apoptosis; D001343:Autophagy / Q000502:physiology*; D002471:Cell Transformation, Neoplastic; D002472:Cell Transformation, Viral / Q000502:physiology*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D018613:Microscopy, Confocal; D009856:Oncogene Proteins, Viral; D027383:Papillomaviridae / Q000378:metabolism; D030361:Papillomavirus Infections / Q000378:metabolism* / Q000473:pathology; D016133:Polymerase Chain Reaction; D014161:Transduction, Genetic; D014162:Transfection; D044763:Ubiquitin-Conjugating Enzymes / Q000378:metabolism*; D000098843:Ubiquitin-Conjugating Enzyme UBC9
chemical_list: D009856:Oncogene Proteins, Viral; D044763:Ubiquitin-Conjugating Enzymes; D000098843:Ubiquitin-Conjugating Enzyme UBC9