title: The anti-proliferative effects of type I IFN involve STAT6-mediated regulation of SP1 and BCL6.
abstract: Type I IFN-induced STAT6 has been shown to have anti-proliferative effects in Daudi and B cells. IFN-sensitive (DS) and IFN-resistant (DR) subclones of Daudi cells were used to study the role of STAT6 in the anti-proliferative activities. Type I IFN significantly increased STAT6 mRNA and protein expression in DS but not DR cells. STAT6 knockdown significantly reduced the sensitivity to IFN in both cell lines. The molecular targets and functional importance of IFN-activated STAT6 were performed by chromatin immunoprecipitation-on-chip (ChIP-on-chip) experiments in type I IFN-treated Daudi cells. Two target genes (Sp1 and BCL6) were selected from the ChIP-on-chip data. IFN-induced STAT6 activation led to Sp1 upregulation and BCL6 downregulation in DS cells, with only minimal effects in DR cells. siRNA inhibition of STAT6 expression resulted in decreased Sp1 and BCL6 mRNA and protein levels in both DS and DR cells. IFN treatment did not increase Sp1 and BCL6 expression in a STAT2-deficient RST2 cell line, and this effect was mitigated by plasmid overexpression of STAT2, indicating that STAT2 is important for STAT6 activation. These results suggest that STAT6 plays an important role in regulating Sp1 and BCL6 through STAT2 to exert the anti-proliferative effects of type I IFN.
authors.affiliation: Institute of Molecular Medicine, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Yu-An
authors.initials: YA
authors.lastname: Hsu
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Chi-Chun
authors.initials: CC
authors.lastname: Huang
authors.affiliation: Department of Veterinary Medicine, National Chung Hsing University, Taichung, Taiwan.
authors.forename: Yung-Jen
authors.initials: YJ
authors.lastname: Kung
authors.affiliation: Department of Ophthalmology, China Medical University Hospital, Taichung, Taiwan; School of Chinese Medicine, China Medical University, Taichung, Taiwan.
authors.forename: Hui-Ju
authors.initials: HJ
authors.lastname: Lin
authors.affiliation: Department of Biotechnology, Asia University, Taichung, Taiwan.
authors.forename: Ching-Yao
authors.initials: CY
authors.lastname: Chang
authors.affiliation: Institute of Molecular Medicine, National Tsing Hua University, Hsinchu, Taiwan. Electronic address: krlee@mx.nthu.edu.tw.
authors.forename: Kuan-Rong
authors.initials: KR
authors.lastname: Lee
authors.affiliation: School of Chinese Medicine, China Medical University, Taichung, Taiwan; Department of Biotechnology, Asia University, Taichung, Taiwan; Department of Gynecology, China Medical University Hospital, Taichung, Taiwan. Electronic address: leiwan@mail.cmu.edu.tw.
authors.forename: Lei
authors.initials: L
authors.lastname: Wan
mesh_terms: D001402:B-Lymphocytes / Q000187:drug effects / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D004268:DNA-Binding Proteins / Q000096:biosynthesis*; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D016898:Interferon-alpha / Q000008:administration & dosage*; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D051560:Proto-Oncogene Proteins c-bcl-6; D050795:STAT2 Transcription Factor / Q000096:biosynthesis* / Q000235:genetics; D050800:STAT6 Transcription Factor / Q000235:genetics*; D015398:Signal Transduction; D016329:Sp1 Transcription Factor / Q000096:biosynthesis*
chemical_list: C084103:BCL6 protein, human; D004268:DNA-Binding Proteins; D016898:Interferon-alpha; D051560:Proto-Oncogene Proteins c-bcl-6; D050795:STAT2 Transcription Factor; C494084:STAT2 protein, human; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D016329:Sp1 Transcription Factor; C108209:SP1 protein, human
keywords: Anti-proliferation activities; BCL6; Interferon alpha; Interferon beta; STAT6; Sp1