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Targeting Gli transcription activation by small molecule suppresses tumor growth

Oncogene volume 33, pages 2087–2097 (2014)Cite this article

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Abstract

Targeted inhibition of Hedgehog signaling at the cell membrane has been associated with anticancer activity in preclinical and early clinical studies. Hedgehog signaling involves activation of Gli transcription factors that can also be induced by alternative pathways. In this study, we identified an interaction between Gli proteins and a transcription coactivator TBP-associated factor 9 (TAF9), and validated its functional relevance in regulating Gli transactivation. We also describe a novel, synthetic small molecule, FN1-8, that efficiently interferes with Gli/TAF9 interaction and downregulate Gli/TAF9-dependent transcriptional activity. More importantly, FN1-8 suppresses cancer cell proliferation in vitro and inhibits tumor growth in vivo. Our results suggest that blocking Gli transactivation, an important control point of multiple oncogenic pathways, may be an effective anticancer strategy.

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Acknowledgements

This work was supported by Joan’s Legacy: Uniting Against Lung Cancer Research Grant, NIH/NCI Grant R01CA125030, and the Eileen D Ludwig Endowed for Thoracic Oncology Research (to BH); NIH/NCI Grant R01CA132566, the Bonnie J Addario Lung Cancer Foundation, the Kazan, McClain, Abrams, Fernandez, Lyons, Greenwood, Harley and Oberman Foundation, Honeywell Foundation and the Barbara Isackson Lung Cancer Research Fund (to DMJ).

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Author notes

  1. G Bosco-Clément and F Zhang: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Surgery, Thoracic Oncology Program, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA

    G Bosco-Clément, F Zhang, Z Chen, H Li, I Mikami, T Hirata, A Yagui-Beltran, N Lui, H T Do, T Cheng, H-H Tseng, H Choi, L-T Fang, I-J Kim, D Yue, Q Zheng, D M Jablons & B He

  2. Division of Life and Health Sciences, Tsinghua University Graduate School at Shenzhen, Shenzhen, China

    F Zhang

  3. School of Life Sciences, Tsinghua University, Beijing, China

    Z Chen & H-M Zhou

  4. Department of Surgery, Division of Thoracic Surgery, Nippon Medical School, Tokyo, Japan

    I Mikami & T Hirata

  5. Department of Lung Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China

    D Yue & C Wang

  6. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Thoracic Surgery II, Peking University Cancer Hospital and Institute, Beijing, China

    Q Zheng

  7. Department of Chemical Biology and Therapeutics, St Jude Children’s Research Hospital, Memphis, TN, USA

    N Fujii

  8. Division of Cardiothoracic Surgery, Department of Surgery, University of California, San Francisco, CA, USA

    M Mann

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  1. G Bosco-Clément
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Correspondence to D M Jablons or B He.

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BH, MM and DMJ have an ownership interest in Rescue Therapeutics. The other authors declare no conflict of interest.

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Bosco-Clément, G., Zhang, F., Chen, Z. et al. Targeting Gli transcription activation by small molecule suppresses tumor growth. Oncogene 33, 2087–2097 (2014). https://doi.org/10.1038/onc.2013.164

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