title: SET7/9 regulates cancer cell proliferation by influencing β-catenin stability.
abstract: β-Catenin, which is a key mediator of the wingless-integration site (Wnt)/β-catenin signaling pathway, plays an important role in cell proliferation, cell fate determination, and tumorigenesis, by regulating the expression of a wide range of target genes. Although a variety of posttranslational modifications are involved in β-catenin activity, the role of lysine methylation in β-catenin activity is largely unknown. In this study, su(var)3-9, enhancer-of-zeste, trithorax (SET) domain-containing protein 7 (SET7/9), a lysine methyltransferase, interacted with and methylated β-catenin, as demonstrated both in vitro and in vivo. The interaction and methylation were significantly enhanced in response to H2O2 stimulation. A mutagenesis assay and mass spectrometric analyses revealed that β-catenin was monomethylated by SET7/9 at lysine residue 180. Methylated β-catenin was easily recognized by phosphokinase glycogen synthase kinase (GSK)-3β for degradation. Consistent with this finding, the mutated β-catenin (K180R) that cannot be methylated exhibited a longer half-life than did the methylated β-catenin. The consequent depletion of SET7/9 by shRNA or the mutation of the β-catenin (K180R) significantly enhanced the expression of Wnt/β-catenin target genes such as c-myc and cyclin D1 and promoted the growth of cancer cells. Together, these results provide a novel mechanism by which Wnt/β-catenin signaling is regulated in response to oxidative stress.
authors.affiliation: *Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing, China; and Peking University-Tsinghua University Center for Life Sciences, Beijing, China.
authors.forename: Changchun
authors.initials: C
authors.lastname: Shen
authors.affiliation: *Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing, China; and Peking University-Tsinghua University Center for Life Sciences, Beijing, China.
authors.forename: Donglai
authors.initials: D
authors.lastname: Wang
authors.affiliation: *Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing, China; and Peking University-Tsinghua University Center for Life Sciences, Beijing, China.
authors.forename: Xiangyu
authors.initials: X
authors.lastname: Liu
authors.affiliation: *Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing, China; and Peking University-Tsinghua University Center for Life Sciences, Beijing, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Gu
authors.affiliation: *Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing, China; and Peking University-Tsinghua University Center for Life Sciences, Beijing, China.
authors.forename: Yipeng
authors.initials: Y
authors.lastname: Du
authors.affiliation: *Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing, China; and Peking University-Tsinghua University Center for Life Sciences, Beijing, China.
authors.forename: Fu-Zheng
authors.initials: FZ
authors.lastname: Wei
authors.affiliation: *Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing, China; and Peking University-Tsinghua University Center for Life Sciences, Beijing, China.
authors.forename: Lin-Lin
authors.initials: LL
authors.lastname: Cao
authors.affiliation: *Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing, China; and Peking University-Tsinghua University Center for Life Sciences, Beijing, China.
authors.forename: Boyan
authors.initials: B
authors.lastname: Song
authors.affiliation: *Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing, China; and Peking University-Tsinghua University Center for Life Sciences, Beijing, China.
authors.forename: Xiaopeng
authors.initials: X
authors.lastname: Lu
authors.affiliation: *Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing, China; and Peking University-Tsinghua University Center for Life Sciences, Beijing, China.
authors.forename: Qiaoyan
authors.initials: Q
authors.lastname: Yang
authors.affiliation: *Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing, China; and Peking University-Tsinghua University Center for Life Sciences, Beijing, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhu
authors.affiliation: *Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing, China; and Peking University-Tsinghua University Center for Life Sciences, Beijing, China.
authors.forename: Tianyun
authors.initials: T
authors.lastname: Hou
authors.affiliation: *Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing, China; and Peking University-Tsinghua University Center for Life Sciences, Beijing, China.
authors.forename: Meiting
authors.initials: M
authors.lastname: Li
authors.affiliation: *Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing, China; and Peking University-Tsinghua University Center for Life Sciences, Beijing, China.
authors.forename: Lina
authors.initials: L
authors.lastname: Wang
authors.affiliation: *Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing, China; and Peking University-Tsinghua University Center for Life Sciences, Beijing, China.
authors.forename: Haiying
authors.initials: H
authors.lastname: Wang
authors.affiliation: *Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing, China; and Peking University-Tsinghua University Center for Life Sciences, Beijing, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: *Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing, China; and Peking University-Tsinghua University Center for Life Sciences, Beijing, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.affiliation: *Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing, China; and Peking University-Tsinghua University Center for Life Sciences, Beijing, China zhuweiguo@bjmu.edu.cn.
authors.forename: Wei-Guo
authors.initials: WG
authors.lastname: Zhu
mesh_terms: D001599:Berberine / Q000494:pharmacology; D015153:Blotting, Western; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D045325:HCT116 Cells; D057809:HEK293 Cells; D006367:HeLa Cells; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008745:Methylation / Q000187:drug effects; D009154:Mutation; D016877:Oxidants / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D055550:Protein Stability; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D034622:RNA Interference; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: D016877:Oxidants; D016271:Proto-Oncogene Proteins c-myc; D051176:beta Catenin; D001599:Berberine; D019938:Cyclin D1; D006861:Hydrogen Peroxide; D011495:Histone-Lysine N-Methyltransferase; C540312:SETD7 protein, human; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3
keywords: Wnt/β-catenin signaling; lysine methylation; oxidative stress