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Conformational stabilization of FOX–DNA complex architecture to sensitize prostate cancer chemotherapy

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Abstract

The forkhead box (FOX) transcription factor is a family of tumor suppressors that negatively regulates the tumorigenesis activity of prostate cancer; stabilization of FOX–DNA complex architecture has been recognized as a new and promising strategy for sensitizing cancer chemotherapy. Here, we described a systematic method that combined in silico analysis and in vitro assay to investigate the intermolecular interaction between FOX DNA-binding domain (DBD) and its cognate DNA partner. The structural and energetic information harvested from the molecular investigation were used to guide high-throughput virtual screening against a structurally diverse, nonredundant library of natural product compounds, aiming at discovery of novel small-molecule medicines that can conformationally stabilize and promote FOX–DNA recognition and interaction. The screening identified a number of theoretically promising hits, which were then examined by using fluorescence anisotropy assay to determine their binding potency for FOX DBD domain. The antitumor activity of identified high-affinity compounds was also tested at cellular level. Structural dynamics analysis found that the small-molecule stabilizers can shift the conformational equilibrium of FOX DBD to DNA-bound state, thus promoting the protein domain to bind tightly with its DNA partner.

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Acknowledgements

This work was supported by The First Affiliated Hospital of Xiamen University.

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  1. Bin Chen and Huiqiang Wang contributed equally to this work.

Authors and Affiliations

  1. Department of Urology and Center of Urology, Xiamen Urinary Center, The First Affiliated Hospital of Xiamen University, Xiamen, 361003, People’s Republic of China

    Bin Chen, Huiqiang Wang, Zhun Wu, Bo Duan, Peide Bai, Kaiyan Zhang, Wei Li, Jiaxin Zheng & Jinchun Xing

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  1. Bin Chen
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Chen, B., Wang, H., Wu, Z. et al. Conformational stabilization of FOX–DNA complex architecture to sensitize prostate cancer chemotherapy. Amino Acids 49, 1247–1254 (2017). https://doi.org/10.1007/s00726-017-2426-1

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