title: Set7 mediated Gli3 methylation plays a positive role in the activation of Sonic Hedgehog pathway in mammals.
abstract: Hedgehog signaling plays very important roles in development and cancers. Vertebrates have three transcriptional factors, Gli1, Gli2 and Gli3. Among them, Gli3 is a very special transcriptional factor which closely resembles Cubitus interruptus (Ci, in Drosophila) structurally and functionally as a 'double agent' for Shh target gene expression. Here we show that Gli3 full-length, but not the truncated form, can be methylated at K436 and K595. This methylation is specifically catalyzed by Set7, a lysine methyltransferase (KMT). Methylation at K436 and K595 respectively increases the stability and DNA binding ability of Gli3, resulting in an enhancement of Shh signaling activation. Furthermore, functional experiments indicate that the Gli3 methylation contributes to the tumor growth and metastasis in non-small cell lung cancer in vitro and in vivo. Therefore, we propose that Set7 mediated methylation is a novel PTM of Gli3, which positively regulates the transactivity of Gli3 and the activation of Shh signaling.
authors.affiliation: State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Innovation Center for Cell Signaling Network, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Fu
authors.affiliation: State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Innovation Center for Cell Signaling Network, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
authors.forename: Hailong
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Developmental Genetics, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China.
authors.forename: Steven Y
authors.initials: SY
authors.lastname: Cheng
authors.affiliation: State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Innovation Center for Cell Signaling Network, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
authors.forename: Daming
authors.initials: D
authors.lastname: Gao
authors.affiliation: State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Innovation Center for Cell Signaling Network, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.|School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Innovation Center for Cell Signaling Network, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.|School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
authors.forename: Yun
authors.identifier: 0000-0002-7807-6094
authors.initials: Y
authors.lastname: Zhao
mesh_terms: D000818:Animals; D063646:Carcinogenesis; D002289:Carcinoma, Non-Small-Cell Lung / Q000503:physiopathology / Q000556:secondary; D004247:DNA / Q000378:metabolism; D004195:Disease Models, Animal; D053823:Hedgehog Proteins / Q000378:metabolism*; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism*; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D008745:Methylation; D051379:Mice; D009362:Neoplasm Metastasis; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D055550:Protein Stability; D015398:Signal Transduction; D000074290:Zinc Finger Protein Gli3
chemical_list: C065683:GLI3 protein, human; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; C509239:SHH protein, human; D000074290:Zinc Finger Protein Gli3; D004247:DNA; D011495:Histone-Lysine N-Methyltransferase; C540312:SETD7 protein, human
keywords: Gli3; Set7; biochemistry; cancer biology; hedgehog signaling; methylation; mouse; tumorigenesis