title: Oncogenic Ras inhibits IRF1 to promote viral oncolysis.
abstract: Oncolytic viruses exploit common molecular changes in cancer cells, which are not present in normal cells, to target and kill cancer cells. Ras transformation and defects in type I interferon (IFN)-mediated antiviral responses are known to be the major mechanisms underlying viral oncolysis. Previously, we demonstrated that oncogenic RAS/Mitogen-activated protein kinase kinase (Ras/MEK) activation suppresses the transcription of many IFN-inducible genes in human cancer cells, suggesting that Ras transformation underlies type I IFN defects in cancer cells. Here, we investigated how Ras/MEK downregulates IFN-induced transcription. By conducting promoter deletion analysis of IFN-inducible genes, namely guanylate-binding protein 2 and IFN gamma inducible protein 47 (Ifi47), we identified the IFN regulatory factor 1 (IRF1) binding site as the promoter region responsible for the regulation of transcription by MEK. MEK inhibition promoted transcription of the IFN-inducible genes in wild type mouse embryonic fibroblasts (MEFs), but not in IRF1(-/-) MEFs, showing that IRF1 is involved in MEK-mediated downregulation of IFN-inducible genes. Furthermore, IRF1 protein expression was lower in RasV12 cells compared with vector control NIH3T3 cells, but was restored to equivalent levels by inhibition of MEK. Similarly, the restoration of IRF1 expression by MEK inhibition was observed in human cancer cells. IRF1 re-expression in human cancer cells caused cells to become resistant to infection by the oncolytic vesicular stomatitis virus strain. Together, this work demonstrates that Ras/MEK activation in cancer cells downregulates transcription of IFN-inducible genes by targeting IRF1 expression, resulting in increased susceptibility to viral oncolysis.
authors.affiliation: Division of BioMedical Sciences, Faculty of Medicine, St John's, Newfoundland, Canada.
authors.forename: Y
authors.initials: Y
authors.lastname: Komatsu
authors.affiliation: Department of Biochemistry, Faculty of Science, Memorial University of Newfoundland, St John's, Newfoundland, Canada.
authors.forename: S L
authors.initials: SL
authors.lastname: Christian
authors.affiliation: Division of BioMedical Sciences, Faculty of Medicine, St John's, Newfoundland, Canada.
authors.forename: N
authors.initials: N
authors.lastname: Ho
authors.affiliation: Division of BioMedical Sciences, Faculty of Medicine, St John's, Newfoundland, Canada.
authors.forename: T
authors.initials: T
authors.lastname: Pongnopparat
authors.affiliation: Division of BioMedical Sciences, Faculty of Medicine, St John's, Newfoundland, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Licursi
authors.affiliation: Division of BioMedical Sciences, Faculty of Medicine, St John's, Newfoundland, Canada.
authors.forename: K
authors.initials: K
authors.lastname: Hirasawa
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000502:physiology*; D007371:Interferon-gamma / Q000502:physiology; D020935:MAP Kinase Signaling System; D051379:Mice; D041681:NIH 3T3 Cells; D050504:Oncolytic Viruses / Q000502:physiology*; D014158:Transcription, Genetic; D018116:Vesiculovirus / Q000502:physiology*; D018631:ras Proteins / Q000502:physiology*
chemical_list: C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; D007371:Interferon-gamma; D018631:ras Proteins