title: JNK and STAT3 signaling pathways converge on Akt-mediated phosphorylation of EZH2 in bronchial epithelial cells induced by arsenic.
abstract: The molecular mechanisms by which arsenic (As ( 3+) ) causes human cancers remain to be fully elucidated. Enhancer of zeste homolog 2 (EZH2) is the catalytic subunit of polycomb-repressive complexes 2 (PRC2) that promotes trimethylation of lysine 27 of histone H3, leading to altered expression of tumor suppressors or oncogenes. In the present study, we determined the effect of As ( 3+)  on EZH2 phosphorylation and the signaling pathways important for As ( 3+) -induced EZH2 phosphorylation in human bronchial epithelial cell line BEAS-2B. The involvement of kinases in As ( 3+) -induced EZH2 phosphorylation was validated by siRNA-based gene silencing. The data showed that As ( 3+)  can induce phosphorylation of EZH2 at serine 21 in human bronchial epithelial cells and that the phosphorylation of EZH2 requires an As ( 3+) -activated signaling cascade from JNK and STAT3 to Akt. Transfection of the cells with siRNA specific for JNK1 revealed that JNK silencing reduced serine727 phosphorylation of STAT3, Akt activation and EZH2 phosphorylation, suggesting that JNK is the upstream kinase involved in As ( 3+) -induced EZH2 phosphorylation. Because As ( 3+)  is capable of inducing miRNA-21 (miR-21), a STAT3-regulated miRNA that represses protein translation of PTEN or Spry2, we also tested the role of STAT3 and miR-21 in As ( 3+) -induced EZH2 phosphorylation. Ectopic overexpression of miR-21 promoted Akt activation and phosphorylation of EZH2, whereas inhibiting miR-21 by transfecting the cells with anti-miR-21 inhibited Akt activation and EZH2 phosphorylation. Taken together, these results demonstrate a contribution of the JNK, STAT3 and Akt signaling axis to As ( 3+) -induced EZH2 phosphorylation. Importantly, these findings may reveal new molecular mechanisms underlying As ( 3+) -induced carcinogenesis.
authors.affiliation: Department of Pharmaceutical Sciences, Wayne State University, Detroit, MI, USA.
authors.forename: Bailing
authors.initials: B
authors.lastname: Chen
authors.forename: Jia
authors.initials: J
authors.lastname: Liu
authors.forename: Qingshan
authors.initials: Q
authors.lastname: Chang
authors.forename: Kevin
authors.initials: K
authors.lastname: Beezhold
authors.forename: Yongju
authors.initials: Y
authors.lastname: Lu
authors.forename: Fei
authors.initials: F
authors.lastname: Chen
mesh_terms: D001151:Arsenic / Q000633:toxicity*; D002460:Cell Line; D000071221:Enhancer of Zeste Homolog 2 Protein; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008565:Membrane Proteins; D035683:MicroRNAs / Q000378:metabolism; D048055:Mitogen-Activated Protein Kinase 8 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D063151:Polycomb Repressive Complex 2 / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D014162:Transfection
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C524940:MIRN21 microRNA, human; D008565:Membrane Proteins; D035683:MicroRNAs; D034741:RNA, Small Interfering; C485561:SPRY2 protein, human; D050796:STAT3 Transcription Factor; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; D051057:Proto-Oncogene Proteins c-akt; D048055:Mitogen-Activated Protein Kinase 8; D001151:Arsenic