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DLC1 deficiency and YAP signaling drive endothelial cell contact inhibition of growth and tumorigenesis

Oncogene volume 38, pages 7046–7059 (2019)Cite this article

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Abstract

Deleted in Liver Cancer 1 (DLC1) is a tumor suppressor gene deleted in many cancers, including angiosarcoma, an aggressive malignancy of endothelial cell derivation. DLC1-deficiency in primary endothelial cells causes the loss of cell contact inhibition of growth through incompletely defined mechanisms. We report that DLC1 is a regulator of YAP, a transcriptional coactivator of proliferation-promoting and tumor-promoting genes; when confluent, active/nuclear YAP was significantly more abundant in DLC1-deficient endothelial cells compared with control cells. We also found that YAP is a required effector of the loss of cell contact inhibition of growth manifested by DLC1-deficient endothelial cells, as the silencing of YAP prevents this loss. Consistently, human angiosarcomas specimens contained a significantly greater proportion of DLC1− tumor cells with nuclear YAP compared with the DLC1+ normal cells in the adjacent tissue. Verteporfin, an inhibitor of YAP, significantly reduced angiosarcoma growth in mice. These results identify YAP as a previously unrecognized effector of DLC1 deficiency-associated loss of cell contact growth inhibition in endothelial cells and a potential therapeutic target in angiosarcoma.

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Acknowledgements

We thank Michael Kruhlak, Langston Lim, and Andy Tran for helping with confocal imaging and images quantification; Ms. Luowei Li, M. DiPrima, Drs. R. Yarchoan, D. Sanchez-Martin, H. Ohnuki, M. Potente, H. Gerhard and Jing-xin Feng; and members of the Laboratory of Cellular Oncology for contributing in various aspects of this work. This work was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research (DSM, XQ, DRL, GT) and by the Japan Society for the Promotion of Science KAKENHI, Grants-in-Aid for Scientific Research 15H05790 (AO, KK).

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  1. These authors contributed equally: Lisa Ritchey and Taekyu Ha

Authors and Affiliations

  1. Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    Lisa Ritchey, Taekyu Ha, Dunrui Wang, Yuyi Wang, Douglas R. Lowy & Giovanna Tosato

  2. Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan

    Atsushi Otsuka & Kenji Kabashima

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LR and TH: design experiments, perform experiments, collection, assembly and interpretation of results, critical review of manuscript; DW: collection of data and data analysis; DL: scientific input, critical evaluation of results, review of manuscript drafts; AO and KK: source of critical patient specimens, patient care and patient information, review of manuscript; YW: performed and evaluated experiments; GT: conception and design, collection and assembly of data, analysis and interpretation of results, writing manuscript.

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Correspondence to Giovanna Tosato.

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Ritchey, L., Ha, T., Otsuka, A. et al. DLC1 deficiency and YAP signaling drive endothelial cell contact inhibition of growth and tumorigenesis. Oncogene 38, 7046–7059 (2019). https://doi.org/10.1038/s41388-019-0944-x

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