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The Hippo pathway transcriptional co-activator, YAP, is an ovarian cancer oncogene

Oncogene volume 30, pages 2810–2822 (2011)Cite this article

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Abstract

The Salvador-Warts-Hippo (SWH) pathway was first discovered in Drosophila melanogaster as a potent inhibitor of tissue growth. The SWH pathway is highly conserved between D. melanogaster and mammals, both in function and in the mechanism of signal transduction. The mammalian SWH pathway limits tissue growth by inhibiting the nuclear access and expression of the transcriptional co-activator, Yes-associated protein (YAP). Mutation and altered expression of SWH pathway proteins has been observed in several types of human cancer, but the contribution of these events to tumorigenesis has been unclear. Here we show that YAP can enhance the transformed phenotype of ovarian cancer cell lines and that YAP confers resistance to chemotherapeutic agents that are commonly used to treat ovarian cancer. We find that high nuclear YAP expression correlates with poor patient prognosis in a cohort of 268 invasive epithelial ovarian cancer samples. Segregation by histotype shows that the correlation between nuclear YAP and poor survival is predominantly associated with clear cell tumors, independent of stage. Collectively our findings suggest that YAP derepression contributes to the genesis of ovarian clear cell carcinoma and that the SWH pathway is an attractive therapeutic target.

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Acknowledgements

We thank the study nurses and research assistants for their contribution to AOCS (http://www.aocstudy.org/) and thank all the women who participated in the study. AOCS was approved by the Human Research Ethics Committees at the Peter Mac, QIMR and participating hospitals. The study was supported by the US Army Medical Research and Materiel Command under DAMD17-01-1-0729, The Cancer Council Victoria, Queensland Cancer Fund, The Cancer Council New South Wales, The Cancer Council South Australia, The Cancer Foundation of Western Australia, The Cancer Council Tasmania and the National Health and Medical Research Council of Australia (NHMRC). We thank D Thomas for comments, D Haber for pBABE-YAP2L and the Peter Mac, Pfizer Incorporated TORCH program for ovarian cancer cell lines. KFH is a Sylvia and Charles Viertel Senior Medical Research Fellow. This work was supported by a Career Development Award from the International Human Frontier Science Program Organization and a Project Grant from the NHMRC of Australia to KFH and the Victorian Breast Cancer Research Consortium to SBF.

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  1. Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

    X Zhang, J George, S Deb, J L Degoutin, E A Takano, S B Fox, D D L Bowtell & K F Harvey

  2. University of Melbourne, Melbourne, Victoria, Australia

    X Zhang, J George, J L Degoutin, D D L Bowtell & K F Harvey

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Correspondence to K F Harvey.

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Zhang, X., George, J., Deb, S. et al. The Hippo pathway transcriptional co-activator, YAP, is an ovarian cancer oncogene. Oncogene 30, 2810–2822 (2011). https://doi.org/10.1038/onc.2011.8

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