title: Suppression of IRF4 by IRF1, 3, and 7 in Noxa expression is a necessary event for IFN-γ-mediated tumor elimination.
abstract: IFN-γ plays a critical role in tumor immunosurveillance by affecting either immune cells or tumor cells; however, IFN-mediated effects on tumor elimination are largely unknown. In this study, we showed that IFN regulatory factors (IRF) modulated by IFNs up- and downregulated Noxa expression, a prodeath BH3 protein, in various cancer cells. Inhibition of Noxa expression using short hairpin RNA in tumor cells leads to resistance against lipopolysaccharide (LPS)-induced tumor elimination, in which IFN-γ is known as a critical effecter in mice. Chromatin immunoprecipitation analysis in both CT26 cells and SP2/0 cells, sensitive and resistant to LPS-induced tumor elimination, respectively, revealed that the responsiveness of IRF1, 3, 4, and 7 in the Noxa promoter region in response to IFN-γ might be crucial in LPS-induced tumor elimination. IRF1, 3, and 7 were upregulated by IFN-γ and activated Noxa expression, leading to the death of Noxa wild-type baby mouse kidney (BMK) cells but not of Noxa-deficient BMK cells. In contrast, IRF4 acts as a repressor for Noxa expression and inhibits cell death induced by IRF1, 3, or 7. Therefore, although IFN-γ alone are not able to induce cell death in tumor cells in vitro, Noxa induction by IFN-γ, which is regulated by the balance between its activators (IRF1, 3, and 7) and its repressor (IRF4), is crucial to increasing the susceptibility of tumor cells to immune cell-mediated cytotoxicity.
authors.affiliation: Department of Biochemistry, Chosun University School of Medicine, Dong-Gu, Gwang-ju 501-759, Korea.
authors.forename: Sujan
authors.initials: S
authors.lastname: Piya
authors.forename: Ae Ran
authors.initials: AR
authors.lastname: Moon
authors.forename: Peter I
authors.initials: PI
authors.lastname: Song
authors.forename: John
authors.initials: J
authors.lastname: Hiscott
authors.forename: Rongtuan
authors.initials: R
authors.lastname: Lin
authors.forename: Dai-Wu
authors.initials: DW
authors.lastname: Seol
authors.forename: Tae-Hyoung
authors.initials: TH
authors.lastname: Kim
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D016923:Cell Death / Q000276:immunology; D004195:Disease Models, Animal; D045325:HCT116 Cells; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000276:immunology; D050838:Interferon Regulatory Factor-3 / Q000276:immunology; D050839:Interferon Regulatory Factor-7 / Q000276:immunology; D050835:Interferon Regulatory Factors / Q000037:antagonists & inhibitors* / Q000276:immunology; D007371:Interferon-gamma / Q000235:genetics*; D019169:Jurkat Cells; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000276:immunology*; D000099218:Interferon Regulatory Factor-4
chemical_list: D051017:Apoptosis Regulatory Proteins; D050856:Interferon Regulatory Factor-1; D050838:Interferon Regulatory Factor-3; D050839:Interferon Regulatory Factor-7; D050835:Interferon Regulatory Factors; D007371:Interferon-gamma; D019253:Proto-Oncogene Proteins c-bcl-2; D000099218:Interferon Regulatory Factor-4; C494257:IRF1 protein, human; C494232:IRF3 protein, human; C494234:IRF7 protein, human; C498702:PMAIP1 protein, human