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Article: Structure and decoy-mediated inhibition of the SOX18/Prox1-DNA interaction

TitleStructure and decoy-mediated inhibition of the SOX18/Prox1-DNA interaction
Authors
Issue Date2016
Citation
Nucleic Acids Research, 2016, v. 44, n. 8, p. 3922-3935 How to Cite?
Abstract© The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research. The transcription factor (TF) SOX18 drives lymphatic vessel development in both embryogenesis and tumour-induced neo-lymphangiogenesis. Genetic disruption of Sox18 in a mouse model protects from tumour metastasis and established the SOX18 protein as a molecular target. Here, we report the crystal structure of the SOX18 DNA binding high-mobility group (HMG) box bound to a DNA element regulating Prox1 transcription. The crystals diffracted to 1.75Å presenting the highest resolution structure of a SOX/DNA complex presently available revealing water structure, structural adjustments at the DNA contact interface and non-canonical conformations of the DNA backbone. To explore alternatives to challenging small molecule approaches for targeting the DNA-binding activity of SOX18, we designed a set of five decoys based on modified Prox1-DNA. Four decoys potently inhibited DNA binding of SOX18 in vitro and did not interact with non-SOX TFs. Serum stability, nuclease resistance and thermal denaturation assays demonstrated that a decoy circularized with a hexaethylene glycol linker and terminal phosphorothioate modifications is most stable. This SOX decoy also interfered with the expression of a luciferase reporter under control of a SOX18-dependent VCAM1 promoter in COS7 cells. Collectively, we propose SOX decoys as potential strategy for inhibiting SOX18 activity to disrupt tumour-induced neo-lymphangiogenesis.
Persistent Identifierhttp://hdl.handle.net/10722/253177
ISSN
2020 Impact Factor: 16.971
2020 SCImago Journal Rankings: 9.008
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorKlaus, Miriam-
dc.contributor.authorProkoph, Nina-
dc.contributor.authorGirbig, Mathias-
dc.contributor.authorWang, Xuecong-
dc.contributor.authorHuang, Yong Heng-
dc.contributor.authorSrivastava, Yogesh-
dc.contributor.authorHou, Linlin-
dc.contributor.authorNarasimhan, Kamesh-
dc.contributor.authorKolatkar, Prasanna R.-
dc.contributor.authorFrancois, Mathias-
dc.contributor.authorJauch, Ralf-
dc.date.accessioned2018-05-11T05:38:49Z-
dc.date.available2018-05-11T05:38:49Z-
dc.date.issued2016-
dc.identifier.citationNucleic Acids Research, 2016, v. 44, n. 8, p. 3922-3935-
dc.identifier.issn0305-1048-
dc.identifier.urihttp://hdl.handle.net/10722/253177-
dc.description.abstract© The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research. The transcription factor (TF) SOX18 drives lymphatic vessel development in both embryogenesis and tumour-induced neo-lymphangiogenesis. Genetic disruption of Sox18 in a mouse model protects from tumour metastasis and established the SOX18 protein as a molecular target. Here, we report the crystal structure of the SOX18 DNA binding high-mobility group (HMG) box bound to a DNA element regulating Prox1 transcription. The crystals diffracted to 1.75Å presenting the highest resolution structure of a SOX/DNA complex presently available revealing water structure, structural adjustments at the DNA contact interface and non-canonical conformations of the DNA backbone. To explore alternatives to challenging small molecule approaches for targeting the DNA-binding activity of SOX18, we designed a set of five decoys based on modified Prox1-DNA. Four decoys potently inhibited DNA binding of SOX18 in vitro and did not interact with non-SOX TFs. Serum stability, nuclease resistance and thermal denaturation assays demonstrated that a decoy circularized with a hexaethylene glycol linker and terminal phosphorothioate modifications is most stable. This SOX decoy also interfered with the expression of a luciferase reporter under control of a SOX18-dependent VCAM1 promoter in COS7 cells. Collectively, we propose SOX decoys as potential strategy for inhibiting SOX18 activity to disrupt tumour-induced neo-lymphangiogenesis.-
dc.languageeng-
dc.relation.ispartofNucleic Acids Research-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.titleStructure and decoy-mediated inhibition of the SOX18/Prox1-DNA interaction-
dc.typeArticle-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1093/nar/gkw130-
dc.identifier.pmid26939885-
dc.identifier.scopuseid_2-s2.0-84966267284-
dc.identifier.volume44-
dc.identifier.issue8-
dc.identifier.spage3922-
dc.identifier.epage3935-
dc.identifier.eissn1362-4962-
dc.identifier.isiWOS:000376389000043-
dc.identifier.issnl0305-1048-

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