Abstract

Over the past decades, the Hippo has been established as a crucial pathway involved in organ size control and cancer suppression. Dysregulation of Hippo signaling and hyperactivation of its downstream effector YAP are frequently associated with various human cancers. However, the underlying significance of such YAP activation in cancer development and therapy has not been fully characterized. In this study, we reported that the Hippo signaling deficiency can lead to a YAP-dependent oncogene addiction for cancer cells. Through a clinical compound library screen, we identified histone deacetylase (HDAC) inhibitors as putative inhibitors to suppress YAP expression. Importantly, HDAC inhibitors specifically targeted the viability and xenograft tumor growth for the cancer cells in which YAP is constitutively active. Taken together, our results not only establish an active YAP-induced oncogene addiction in cancer cells, but also lay the foundation to develop targeted therapies for the cancers with Hippo dysfunction and YAP activation.

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Acknowledgements

We thank Drs. Steven H Lin and Junjie Chen (MD Anderson Cancer Center) for the clinical compound library. WW is a recipient of an American Association for Cancer Research Career Development Award for Translational Breast Cancer Research supported by the Breast Cancer Research Foundation (16-20-26-WANG). This work was supported by University of California, Irvine Chao Family Comprehensive Cancer Center (Pilot Project 2018) and in part by a NIH grant (R01 GM126048) and a Research Scholar Grant (RSG-18-009-01-CCG) from the American Cancer Society to WW.

Author contributions

WW conceived and supervised study. HH and WW designed the experiments and analyzed the data. HH and BY performed all the experiments with the assistance from HJN, JY, YZ, KLN, ATB and TKM. WW wrote the manuscript.

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  1. Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA, 92697, USA

    • Han Han
    • , Bing Yang
    • , Hiroki J Nakaoka
    • , Jiadong Yang
    • , Yifan Zhao
    • , Kathern Le Nguyen
    • , Amell Taffy Bishara
    • , Tejas Krishen Mandalia
    •  & Wenqi Wang

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The authors declare that they have no conflict of interest.

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Correspondence to Wenqi Wang.

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https://doi.org/10.1038/s41388-018-0419-5