title: Downregulation of transcription factor E4F1 in hepatocarcinoma cells: HBV-dependent effects on autophagy, proliferation and metabolism.
abstract: The multifunctional E4F1 protein is a cellular target of the E1A adenoviral oncoprotein. Interaction between E4F1 and the hepatitis B virus (HBV) protein HBx has been demonstrated in vitro. In this study, RNA interference has been used to downregulate E4F1 in the hepatocellular carcinoma (HCC) cell line HepG2 (HBV negative) and its derivative, HBV expressing HepG2/2.2.15. Reduction of E4F1 levels induced hepatocyte vacuolation (formation of large cytoplasmic vesicles), increased autophagy and caused mitochondrial defects and metabolism changes in HepG2/2.2.15, but not in HepG2. Moreover, downregulation of E4F1 reduced DNA synthesis with partial cell cycle arrest in G1 in both cell types and this effect was more marked in HepG2/2.2.15 than in HepG2. These effects were partially prevented by RNA interference directed to either HBx or to p53. Coprecipitation and western blot experiments detected complexes between E4F1 and HBx in several HCC cell lines. Although a review of mutation and gene expression public databases did not support that E4F1 is specifically altered in liver cancer, our results suggest that E4F1 may neutralize the capacity of HBx to activate a p53-dependent, metabolic and growth arrest phenotype in liver cells, thus possibly contributing to the viability and proliferation of HBV-infected cells.
authors.affiliation: Molecular Carcinogenesis, International Agency for Research on Cancer, 150 Cours Albert Thomas, Lyon 69372, France.
authors.forename: Yayun
authors.initials: Y
authors.lastname: Dai
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Cros
authors.forename: Clément
authors.initials: C
authors.lastname: Pontoizeau
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Elena-Hermann
authors.forename: Günther K
authors.initials: GK
authors.lastname: Bonn
authors.forename: Pierre
authors.initials: P
authors.lastname: Hainaut
mesh_terms: D001343:Autophagy; D001483:Base Sequence; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003593:Cytoplasm / Q000378:metabolism; D051268:GA-Binding Protein Transcription Factor / Q000378:metabolism*; D006515:Hepatitis B virus / Q000502:physiology*; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D019906:Nuclear Magnetic Resonance, Biomolecular; D034741:RNA, Small Interfering
chemical_list: C079860:E4TF1 transcription factor; D051268:GA-Binding Protein Transcription Factor; D034741:RNA, Small Interfering