title: SND1 acts as a novel gene transcription activator recognizing the conserved Motif domains of Smad promoters, inducing TGFβ1 response and breast cancer metastasis.
abstract: As an AEG-1/MTDH/LYRIC-binding protein, Staphylococcal nuclease domain-containing 1 (SND1) is upregulated in numerous human cancers where it has been assigned multiple functional roles. In this study, we discovered that SND1 was upregulated in breast cancer tissues, particularly the tissues from patients with distant metastases. The underlying molecular mechanisms demonstrated a novel role of SND1 in regulating the activity of transforming growth factor β1 (TGFβ1) signaling pathway, which promotes metastasis in breast cancer. We illustrated that SND1 physically associated with and recruited the histone acetylase GCN5 to the promoter regions of Smad2/3/4, and consequently enhanced the gene transcriptional activation of Smad2/3/4, which are essential downstream regulators in the TGFβ1 pathway. An electrophoretic mobility shift assay experiment further verified that SND1 could recognize the conserved domains (motifs 1 and 2) in the promoter regions of the Smad genes. Glutathione S-transferase (GST) pulldown assays indicated that the tudor domain of SND1 was responsible for the recruitment of GCN5, which increased histone H3K9 acetylation. Consistent with these results, a loss-of-function of SND1 reduced the protein level of Smads and the phosphorylation of R-Smads, thereby attenuating the R-Smad/Co-Smad depended transcription and, as a result, inhibited TGFβ signaling activation.
authors.affiliation: Department of Biochemistry and Molecular Biology, Tianjin Medical University, Tianjin, China.|Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.|Laboratory of Molecular Immunology, Research Center of Basic Medical Science, Tianjin Medical University, Tianjin, China.|Key Laboratory of the Educational Ministry of China, Tianjin Medical University, Tianjin, China.|Tianjin Key Laboratory of Cellular and Molecular Immunology, Tianjin Medical University, Tianjin, China.
authors.forename: L
authors.initials: L
authors.lastname: Yu
authors.affiliation: Department of Biochemistry and Molecular Biology, Tianjin Medical University, Tianjin, China.|Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.|Laboratory of Molecular Immunology, Research Center of Basic Medical Science, Tianjin Medical University, Tianjin, China.|Key Laboratory of the Educational Ministry of China, Tianjin Medical University, Tianjin, China.|Tianjin Key Laboratory of Cellular and Molecular Immunology, Tianjin Medical University, Tianjin, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Di
authors.affiliation: Department of Biochemistry and Molecular Biology, Tianjin Medical University, Tianjin, China.|Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.|Laboratory of Molecular Immunology, Research Center of Basic Medical Science, Tianjin Medical University, Tianjin, China.|Key Laboratory of the Educational Ministry of China, Tianjin Medical University, Tianjin, China.|Tianjin Key Laboratory of Cellular and Molecular Immunology, Tianjin Medical University, Tianjin, China.
authors.forename: L
authors.initials: L
authors.lastname: Xin
authors.affiliation: Department of Biochemistry and Molecular Biology, Tianjin Medical University, Tianjin, China.|Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.|Laboratory of Molecular Immunology, Research Center of Basic Medical Science, Tianjin Medical University, Tianjin, China.|Key Laboratory of the Educational Ministry of China, Tianjin Medical University, Tianjin, China.|Tianjin Key Laboratory of Cellular and Molecular Immunology, Tianjin Medical University, Tianjin, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Ren
authors.affiliation: Department of Biochemistry and Molecular Biology, Tianjin Medical University, Tianjin, China.|Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.|Laboratory of Molecular Immunology, Research Center of Basic Medical Science, Tianjin Medical University, Tianjin, China.|Key Laboratory of the Educational Ministry of China, Tianjin Medical University, Tianjin, China.|Tianjin Key Laboratory of Cellular and Molecular Immunology, Tianjin Medical University, Tianjin, China.
authors.forename: X
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Biochemistry and Molecular Biology, Tianjin Medical University, Tianjin, China.|Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.|Laboratory of Molecular Immunology, Research Center of Basic Medical Science, Tianjin Medical University, Tianjin, China.|Key Laboratory of the Educational Ministry of China, Tianjin Medical University, Tianjin, China.|Tianjin Key Laboratory of Cellular and Molecular Immunology, Tianjin Medical University, Tianjin, China.
authors.forename: X
authors.initials: X
authors.lastname: Sun
authors.affiliation: Department of Biochemistry and Molecular Biology, Tianjin Medical University, Tianjin, China.|Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.|Laboratory of Molecular Immunology, Research Center of Basic Medical Science, Tianjin Medical University, Tianjin, China.|Key Laboratory of the Educational Ministry of China, Tianjin Medical University, Tianjin, China.|Tianjin Key Laboratory of Cellular and Molecular Immunology, Tianjin Medical University, Tianjin, China.
authors.forename: W
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.|Laboratory of Molecular Immunology, Research Center of Basic Medical Science, Tianjin Medical University, Tianjin, China.|Key Laboratory of the Educational Ministry of China, Tianjin Medical University, Tianjin, China.|Tianjin Key Laboratory of Cellular and Molecular Immunology, Tianjin Medical University, Tianjin, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Yao
authors.affiliation: Department of Biochemistry and Molecular Biology, Tianjin Medical University, Tianjin, China.|Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.|Laboratory of Molecular Immunology, Research Center of Basic Medical Science, Tianjin Medical University, Tianjin, China.|Key Laboratory of the Educational Ministry of China, Tianjin Medical University, Tianjin, China.|Tianjin Key Laboratory of Cellular and Molecular Immunology, Tianjin Medical University, Tianjin, China.
authors.forename: J
authors.initials: J
authors.lastname: Yang
mesh_terms: D000818:Animals; D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D002465:Cell Movement; D017124:Conserved Sequence; D004720:Endonucleases; D005260:Female; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000556:secondary; D008207:Lymphatic Metastasis; D061986:MCF-7 Cells; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D009687:Nuclear Proteins / Q000502:physiology*; D011379:Prognosis; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D051785:Smad Proteins / Q000235:genetics; D015533:Transcriptional Activation; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D050880:p300-CBP Transcription Factors / Q000378:metabolism; D000099224:p300-CBP-Associated Factor
chemical_list: D004720:Endonucleases; D009687:Nuclear Proteins; D051785:Smad Proteins; D053773:Transforming Growth Factor beta1; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C508960:TGFB1 protein, human; C095221:SND1 protein, human