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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Siegel R, Naishadham D, Jemal A . Cancer statistics, 2013. CA Cancer J Clin 2013; 63: 11–30.
Stein JP, Lieskovsky G, Cote R, Groshen S, Feng AC, Boyd S et al. Radical cystectomy in the treatment of invasive bladder cancer: long-term results in 1,054 patients. J Clin Oncol 2001; 19: 666–675.
Madersbacher S, Hochreiter W, Burkhard F, Thalmann GN, Danuser H, Markwalder R et al. Radical cystectomy for bladder cancer today–a homogeneous series without neoadjuvant therapy. J Clin Oncol 2003; 21: 690–696.
von der Maase H, Hansen SW, Roberts JT, Dogliotti L, Oliver T, Moore MJ et al. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol 2000; 18: 3068–3077.
Grossman HB, Natale RB, Tangen CM, Speights VO, Vogelzang NJ, Trump DL et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med 2003; 349: 859–866.
Shah JB, McConkey DJ, Dinney CP . New strategies in muscle-invasive bladder cancer: on the road to personalized medicine. Clin Cancer Res 2011; 17: 2608–2612.
Galluzzi L, Senovilla L, Vitale I, Michels J, Martins I, Kepp O et al. Molecular mechanisms of cisplatin resistance. Oncogene 2012; 31: 1869–1883.
Harvey KF, Zhang X, Thomas DM . The Hippo pathway and human cancer. Nat Rev Cancer 2013; 13: 246–257.
Zhao B, Li L, Tumaneng K, Wang CY, Guan KL . A coordinated phosphorylation by Lats and CK1 regulates YAP stability through SCF(beta-TRCP). Genes Dev 2010; 24: 72–85.
Zhao B, Ye X, Yu J, Li L, Li W, Li S et al. TEAD mediates YAP-dependent gene induction and growth control. Genes Dev 2008; 22: 1962–1971.
Overholtzer M, Zhang J, Smolen GA, Muir B, Li W, Sgroi DC et al. Transforming properties of YAP, a candidate oncogene on the chromosome 11q22 amplicon. Proc Natl Acad Sci USA 2006; 103: 12405–12410.
Zender L, Spector MS, Xue W, Flemming P, Cordon-Cardo C, Silke J et al. Identification and validation of oncogenes in liver cancer using an integrative oncogenomic approach. Cell 2006; 125: 1253–1267.
Camargo FD, Gokhale S, Johnnidis JB, Fu D, Bell GW, Jaenisch R et al. YAP1 increases organ size and expands undifferentiated progenitor cells. Curr Biol 2007; 17: 2054–2060.
Dong J, Feldmann G, Huang J, Wu S, Zhang N, Comerford SA et al. Elucidation of a universal size-control mechanism in Drosophila and mammals. Cell 2007; 130: 1120–1133.
Zhang J, Ji JY, Yu M, Overholtzer M, Smolen GA, Wang R et al. YAP-dependent induction of amphiregulin identifies a non-cell-autonomous component of the Hippo pathway. Nature Cell Biol 2009; 11: 1444–1450.
Fernandez LA, Squatrito M, Northcott P, Awan A, Holland EC, Taylor MD et al. Oncogenic YAP promotes radioresistance and genomic instability in medulloblastoma through IGF2-mediated Akt activation. Oncogene 2012; 31: 1923–1937.
Hall CA, Wang R, Miao J, Oliva E, Shen X, Wheeler T et al. Hippo pathway effector Yap is an ovarian cancer oncogene. Cancer Res 2010; 70: 8517–8525.
Zhang X, George J, Deb S, Degoutin JL, Takano EA, Fox SB et al. The Hippo pathway transcriptional co-activator, YAP, is an ovarian cancer oncogene. Oncogene 2011; 30: 2810–2822.
Proctor AJ, Coombs LM, Cairns JP, Knowles MA . Amplification at chromosome 11q13 in transitional cell tumours of the bladder. Oncogene 1991; 6: 789–795.
Liu JY, Li YH, Lin HX, Liao YJ, Mai SJ, Liu ZW et al. Overexpression of YAP 1 contributes to progressive features and poor prognosis of human urothelial carcinoma of the bladder. BMC Cancer 2013; 13: 349.
Strano S, Munarriz E, Rossi M, Castagnoli L, Shaul Y, Sacchi A et al. Physical interaction with Yes-associated protein enhances p73 transcriptional activity. J Biol Chem 2001; 276: 15164–15173.
Basu S, Totty NF, Irwin MS, Sudol M, Downward J . Akt phosphorylates the Yes-associated protein, YAP, to induce interaction with 14-3-3 and attenuation of p73-mediated apoptosis. Mol Cell 2003; 11: 11–23.
Yuan M, Tomlinson V, Lara R, Holliday D, Chelala C, Harada T et al. Yes-associated protein (YAP) functions as a tumor suppressor in breast. Cell Death Differ 2008; 15: 1752–1759.
Ehsanian R, Brown M, Lu H, Yang XP, Pattatheyil A, Yan B et al. YAP dysregulation by phosphorylation or DeltaNp63-mediated gene repression promotes proliferation, survival and migration in head and neck cancer subsets. Oncogene 2010; 29: 6160–6171.
Imanaka Y, Tsuchiya S, Sato F, Shimada Y, Shimizu K, Tsujimoto G . MicroRNA-141 confers resistance to cisplatin-induced apoptosis by targeting YAP1 in human esophageal squamous cell carcinoma. J Hum Genet 2011; 56: 270–276.
Torti D, Trusolino L . Oncogene addiction as a foundational rationale for targeted anti-cancer therapy: promises and perils. EMBO Mol Med 2011; 3: 623–636.
Roos WP, Kaina B . DNA damage-induced cell death: from specific DNA lesions to the DNA damage response and apoptosis. Cancer Lett 2013; 332: 237–248.
Zhou BB, Elledge SJ . The DNA damage response: putting checkpoints in perspective. Nature 2000; 408: 433–439.
Liu-Chittenden Y, Huang B, Shim JS, Chen Q, Lee SJ, Anders RA et al. Genetic and pharmacological disruption of the TEAD-YAP complex suppresses the oncogenic activity of YAP. Genes Dev 2012; 26: 1300–1305.
Bressler NM, Bressler SB . Photodynamic therapy with verteporfin (Visudyne): impact on ophthalmology and visual sciences. Invest Ophthalmol Vis Sci 2000; 41: 624–628.
Belyanskaya LL, Hopkins-Donaldson S, Kurtz S, Simoes-Wust AP, Yousefi S, Simon HU et al. Cisplatin activates Akt in small cell lung cancer cells and attenuates apoptosis by survivin upregulation. Int J Cancer 2005; 117: 755–763.
Sun XP, Dong X, Lin L, Jiang X, Wei Z, Zhai B et al. Up-regulation of survivin by AKT and hypoxia-inducible factor 1alpha contributes to cisplatin resistance in gastric cancer. FEBS J 2014; 281: 115–128.
Pollack A, Wu CS, Czerniak B, Zagars GK, Benedict WF, McDonnell TJ . Abnormal bcl-2 and pRb expression are independent correlates of radiation response in muscle-invasive bladder cancer. Clin Cancer Res 1997; 3: 1823–1829.
Cote RJ, Esrig D, Groshen S, Jones PA, Skinner DG . p53 and treatment of bladder cancer. Nature 1997; 385: 123–125.
Choi W, Porten S, Kim S, Willis D, Plimack ER, Hoffman-Censits J et al. Identification of distinct basal and luminal subtypes of muscle-invasive bladder cancer with different sensitivities to frontline chemotherapy. Cancer Cell 2014; 25: 152–165.
Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov 2012; 2: 401–404.
Lai D, Ho KC, Hao Y, Yang X . Taxol resistance in breast cancer cells is mediated by the hippo pathway component TAZ and its downstream transcriptional targets Cyr61 and CTGF. Cancer Res 2011; 71: 2728–2738.
Huang JM, Nagatomo I, Suzuki E, Mizuno T, Kumagai T, Berezov A et al. YAP modifies cancer cell sensitivity to EGFR and survivin inhibitors and is negatively regulated by the non-receptor type protein tyrosine phosphatase 14. Oncogene 2013; 32: 2220–2229.
Zhao Y, Khanal P, Savage P, She YM, Cyr TD, Yang X . YAP-induced resistance of cancer cells to antitubulin drugs is modulated by a hippo-independent pathway. Cancer Res 2014; 74: 4493–4503.
Sheen-Chen SM, Huang CY, Tsai CH, Liu YW, Wu SC, Huang CC et al. Yes-associated protein is not an independent prognostic marker in breast cancer. Anticancer Res 2012; 32: 3321–3325.
Xu MZ, Yao TJ, Lee NP, Ng IO, Chan YT, Zender L et al. Yes-associated protein is an independent prognostic marker in hepatocellular carcinoma. Cancer 2009; 115: 4576–4585.
Reichert S, Rodel C, Mirsch J, Harter PN, Tomicic MT, Mittelbronn M et al. Survivin inhibition and DNA double-strand break repair: a molecular mechanism to overcome radioresistance in glioblastoma. Radiother Oncol 2011; 101: 51–58.
Wang MY, Chen PS, Prakash E, Hsu HC, Huang HY, Lin MT et al. Connective tissue growth factor confers drug resistance in breast cancer through concomitant up-regulation of Bcl-xL and cIAP1. Cancer Res 2009; 69: 3482–3491.
Tsai HC, Huang CY, Su HL, Tang CH . CCN2 enhances resistance to cisplatin-mediating cell apoptosis in human osteosarcoma. PLoS One 2014; 9: e90159.
Todorovic V, Chen CC, Hay N, Lau LF . The matrix protein CCN1 (CYR61) induces apoptosis in fibroblasts. J Cell Biol 2005; 171: 559–568.
Lin MT, Chang CC, Chen ST, Chang HL, Su JL, Chau YP et al. Cyr61 expression confers resistance to apoptosis in breast cancer MCF-7 cells by a mechanism of NF-kappaB-dependent XIAP up-regulation. J Biol Chem 2004; 279: 24015–24023.
Damrauer JS, Hoadley KA, Chism DD, Fan C, Tiganelli CJ, Wobker SE et al. Intrinsic subtypes of high-grade bladder cancer reflect the hallmarks of breast cancer biology. Proc Natl Acad Sci USA 2014; 111: 3110–3115.
Jiang N, Hjorth-Jensen K, Hekmat O, Iglesias-Gato D, Kruse T, Wang C et al. In vivo quantitative phosphoproteomic profiling identifies novel regulators of castration-resistant prostate cancer growth. Oncogene 2014; 34: 2764–2776.
Yu FX, Luo J, Mo JS, Liu G, Kim YC, Meng Z et al. Mutant Gq/11 promote uveal melanoma tumorigenesis by activating YAP. Cancer Cell 2014; 25: 822–830.
Feng X, Degese MS, Iglesias-Bartolome R, Vaque JP, Molinolo AA, Rodrigues M et al. Hippo-independent activation of YAP by the GNAQ uveal melanoma oncogene through a trio-regulated rho GTPase signaling circuitry. Cancer Cell 2014; 25: 831–845.
Liu X, Ory V, Chapman S, Yuan H, Albanese C, Kallakury B et al. ROCK inhibitor and feeder cells induce the conditional reprogramming of epithelial cells. Am J Pathol 2012; 180: 599–607.
Liao W, McNutt MA, Zhu WG . The comet assay: a sensitive method for detecting DNA damage in individual cells. Methods 2009; 48: 46–53.
Ciamporcero E, Miles KM, Adelaiye R, Ramakrishnan S, Shen L, Ku SY et al. Combination strategy targeting VEGF and HGF/c-met in human renal cell carcinoma models. Mol Cancer Ther 2014; 14: 101–110.
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.
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Additional information
This study was in part previously presented at the 2014 American Association for Cancer Research Annual Meeting.
Supplementary Information accompanies this paper on the Oncogene website
Supplementary information
Rights and permissions
About this article
Cite this article
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
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/onc.2015.219
This article is cited by
-
The biology of YAP in programmed cell death
Biomarker Research (2022)
-
An innovative targeted therapy for fluoroscopy-induced chronic radiation dermatitis
Journal of Molecular Medicine (2022)
-
MINDY1 promotes bladder cancer progression by stabilizing YAP
Cancer Cell International (2021)
-
Radiation-induced YAP activation confers glioma radioresistance via promoting FGF2 transcription and DNA damage repair
Oncogene (2021)
-
YAP promotes sorafenib resistance in hepatocellular carcinoma by upregulating survivin
Cellular Oncology (2021)