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YAP activation protects urothelial cell carcinoma from treatment-induced DNA damage

Oncogene volume 35, pages 1541–1553 (2016)Cite this article

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Abstract

Current standard of care for muscle-invasive urothelial cell carcinoma (UCC) is surgery along with perioperative platinum-based chemotherapy. UCC is sensitive to cisplatin-based regimens, but acquired resistance eventually occurs, and a subset of tumors is intrinsically resistant. Thus, there is an unmet need for new therapeutic approaches to target chemotherapy-resistant UCC. Yes-associated protein (YAP) is a transcriptional co-activator that has been associated with bladder cancer progression and cisplatin resistance in ovarian cancer. In contrast, YAP has been shown to induce DNA damage associated apoptosis in non-small cell lung carcinoma. However, no data have been reported on the YAP role in UCC chemo-resistance. Thus, we have investigated the potential dichotomous role of YAP in UCC response to chemotherapy utilizing two patient-derived xenograft models recently established. Constitutive expression and activation of YAP inversely correlated with in vitro and in vivo cisplatin sensitivity. YAP overexpression protected while YAP knockdown sensitized UCC cells to chemotherapy and radiation effects via increased accumulation of DNA damage and apoptosis. Furthermore, pharmacological YAP inhibition with verteporfin inhibited tumor cell proliferation and restored sensitivity to cisplatin. In addition, nuclear YAP expression was associated with poor outcome in UCC patients who received perioperative chemotherapy. In conclusion, these results suggest that YAP activation exerts a protective role and represents a pharmacological target to enhance the anti-tumor effects of DNA damaging modalities in the treatment of UCC.

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Acknowledgements

This study was in part supported by the National Cancer Institute P30 CA016056 (RP), R21 CA179693 (JZ), the American Cancer Society 127226-RSG-14-214-01-TBE (JZ) and a research donation from Richard Di Vita and family (RP). We thank the MTMR and Pathology Core Facilities at Roswell Park Cancer Institute for processing the tissue samples.

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Authors and Affiliations

  1. Department of Medicine, Genitourinary Program, Roswell Park Cancer Institute, Buffalo, NY, USA

    E Ciamporcero, S Ramakrishnan, S Yu Ku, S Chintala, L Shen, R Adelaiye, K M Miles, C Johnson & R Pili

  2. Department of Clinical and Biological Sciences, University of Turin, Turin, Italy

    E Ciamporcero, C Ullio, S Pizzimenti, M Daga & G Barrera

  3. Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY, USA

    H Shen & J Zhang

  4. Department of Cancer Pathology & Prevention, Roswell Park Cancer Institute, Buffalo, NY, USA

    S Ramakrishnan, S Yu Ku & R Adelaiye

  5. Department of Pharmacology & Therapeutics, Roswell Park Cancer Institute, Buffalo, NY, USA

    S Chintala & C Johnson

  6. Department of Pathology, Roswell Park Cancer Institute, Buffalo, NY, USA

    G Azabdaftari

  7. Department of Biostatistics & Bioinformatics, Roswell Park Cancer Institute, Buffalo, NY, USA

    K Attwood

  8. Department of Medicine, Indiana University, Indianapolis, IN, USA

    R Pili

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Correspondence to G Barrera or R Pili.

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This study was in part previously presented at the 2014 American Association for Cancer Research Annual Meeting.

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Ciamporcero, E., Shen, H., Ramakrishnan, S. et al. YAP activation protects urothelial cell carcinoma from treatment-induced DNA damage. Oncogene 35, 1541–1553 (2016). https://doi.org/10.1038/onc.2015.219

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