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

Miriam Klaus, Nina Prokoph, Mathias Girbig, Xuecong Wang, Yong Heng Huang, Yogesh Srivastava, Linlin Hou, Kamesh Narasimhan, Prasanna Kolatkar, Mathias Francois, Ralf Jauch

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)3922-3935
Number of pages14
JournalNucleic Acids Research
Volume44
Issue number8
DOIs
Publication statusPublished - 5 May 2016

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DNA
Lymphangiogenesis
SOXF Transcription Factors
Nucleic Acid Conformation
Neoplasms
Lymphatic Vessels
Luciferases
Embryonic Development
Hot Temperature
Neoplasm Metastasis
Water
Serum
Proteins

ASJC Scopus subject areas

  • Genetics

Cite this

Klaus, M., Prokoph, N., Girbig, M., Wang, X., Huang, Y. H., Srivastava, Y., ... Jauch, R. (2016). Structure and decoy-mediated inhibition of the SOX18/Prox1-DNA interaction. Nucleic Acids Research, 44(8), 3922-3935. https://doi.org/10.1093/nar/gkw130

Structure and decoy-mediated inhibition of the SOX18/Prox1-DNA interaction. / Klaus, Miriam; Prokoph, Nina; Girbig, Mathias; Wang, Xuecong; Huang, Yong Heng; Srivastava, Yogesh; Hou, Linlin; Narasimhan, Kamesh; Kolatkar, Prasanna; Francois, Mathias; Jauch, Ralf.

In: Nucleic Acids Research, Vol. 44, No. 8, 05.05.2016, p. 3922-3935.

Research output: Contribution to journalArticle

Klaus, M, Prokoph, N, Girbig, M, Wang, X, Huang, YH, Srivastava, Y, Hou, L, Narasimhan, K, Kolatkar, P, Francois, M & Jauch, R 2016, 'Structure and decoy-mediated inhibition of the SOX18/Prox1-DNA interaction', Nucleic Acids Research, vol. 44, no. 8, pp. 3922-3935. https://doi.org/10.1093/nar/gkw130
Klaus M, Prokoph N, Girbig M, Wang X, Huang YH, Srivastava Y et al. Structure and decoy-mediated inhibition of the SOX18/Prox1-DNA interaction. Nucleic Acids Research. 2016 May 5;44(8):3922-3935. https://doi.org/10.1093/nar/gkw130
Klaus, Miriam ; Prokoph, Nina ; Girbig, Mathias ; Wang, Xuecong ; Huang, Yong Heng ; Srivastava, Yogesh ; Hou, Linlin ; Narasimhan, Kamesh ; Kolatkar, Prasanna ; Francois, Mathias ; Jauch, Ralf. / Structure and decoy-mediated inhibition of the SOX18/Prox1-DNA interaction. In: Nucleic Acids Research. 2016 ; Vol. 44, No. 8. pp. 3922-3935.
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