Abstract
The Yes Associated Protein 1 (YAP1) is a transcriptional cofactor negatively regulated by Hippo Pathway. The dysregulation of the pathway has been shown to have a role in tumorigenesis and metastasis in several cancers including prostate cancer (PCa). In this study, YAP1 expression was upregulated in the whole cell lysates and cytoplasmic/nuclear extracts of AR negative (PC3) compared to AR positive (LNCaP) prostate cancer cell lines and primary prostate epithelial cells (PrePEC). pYAP1 expression elevated in LNCaP compared to PC3 and PrePEC in whole cell lysates and cytoplasmic extracts. The treatment of LNCaP and PC3 with YAP1-targeting siRNA oligonucleotides (YAP1 siRNA) significantly reduced their proliferation in vitro. Furthermore, treatment with YAP1 siRNA diminished the clonogenicity, anchorage-independent growth on soft agar, migration and invasion of PC3 cells. Co-IP/WB experiments revealed that YAP1 and AR formed a complex and ChIP/PCR results confirmed that YAP1 was bound to androgen response elements (ARE) core region of the prostate specific antigen (PSA) promoter. The loss of function experiments in LNCaP and PC3 revealed that YAP1 regulates proliferation, colony formation as well as anchorage-independent growth and potentially plays an important role in migration and invasion. Finally, analysis of publicly available data sets indicated that LNCaP had no YAP1 copy number alteration whereas PC3 had gain of YAP1 which was also reflected as an increase in the mRNA level. Moreover, YAP1 copy number gain and elevated YAP1 mRNA expression were detected in clinical samples analyzed in publicly available data sets. Taken together, these results suggested that YAP1 has a role in PCa tumorigenesis.
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References
Harvey KF, Pfleger CM, Hariharan IK (2003) The Drosophila Mst ortholog, hippo, restricts growth and cell proliferation and promotes apoptosis. Cell. 114:457–467
Mahoney JE, Mori M, Szymaniak AD, Varelas X, Cardoso W (2014) The hippo pathway effector yap controls patterning and differentiation of airway epithelial progenitors. Dev Cell 30:137–150
Zhao B, Wei X, Li W, Udan RS, Yang Q, Kim J, et al. Inactivation of YAP oncoprotein by the hippo pathway is involved in cell contact inhibition and tissue growth control. 2007;2747–61
Ehmer U, Sage J (2016) Control of proliferation and Cancer growth by the hippo signaling pathway. Mol Cancer Res 14:127–140
Zhao B, Ye X, Yu J, Li L, Li W, Li S, Yu J, Lin JD, Wang CY, Chinnaiyan AM, Lai ZC, Guan KL (2008) TEAD mediates YAP-dependent gene induction and growth control. Genes Dev 22:1962–1971
Alarcon C, Zaromytidou A-I, Xi Q, Gao S, Yu J, Fujisawa S et al (2009) Nuclear CDKs drive Smad transcriptional activation and turnover in BMP and TGF- pathways. Cell. 139:757–769
Strano S, Munarriz E, Rossi M, Castagnoli L, Shaul Y, Sacchi A, Oren M, Sudol M, Cesareni G, Blandino G (2001) Physical interaction with yes-associated protein enhances p73 transcriptional activity. J Biol Chem 276:15164–15173
Haskins JW, Nguyen DX, Stern DF (2014) Neuregulin 1-activated ERBB4 interacts with YAP to induce hippo pathway target genes and promote cell migration. Sci Signal 7:ra116
Attard G, Parker C, Eeles RA, Schröder F, Tomlins SA, Tannock I, Drake CG, de Bono JS (2016) Prostate cancer. Lancet. 387:70–82
Disibio G, French SW (2008) Metastatic patterns of cancers: results from a large autopsy study. Arch Pathol Lab Med 132:931–939
Schrecengost R, Knudsen KE (2013) Molecular pathogenesis and progression of prostate Cancer. Semin Oncol 40:244–258
Hu X, Jia Y, Yu J, Chen J, Fu Q (2015) Loss of YAP protein in prostate cancer is associated with Gleason score increase. Tumori. 101:189–193
Yuan M, Tomlinson V, Lara R, Holliday D, Chelala C, Harada T, Gangeswaran R, Manson-Bishop C, Smith P, Danovi SA, Pardo O, Crook T, Mein CA, Lemoine NR, Jones LJ, Basu S (2008) Yes-associated protein (YAP) functions as a tumor suppressor in breast. Cell Death Differ 15:1752–1759
Wang Y, Dong Q, Zhang Q, Li Z, Wang E, Qiu X (2010) Overexpression of yes-associated protein contributes to progression and poor prognosis of non-small-cell lung cancer. Cancer Sci 101:1279–1285
Xu MZ, Yao T-J, Lee NPY, Ng IOL, Chan Y-T, Zender L, Lowe SW, Poon RTP, Luk JM (2009) Yes-associated protein is an independent prognostic marker in hepatocellular carcinoma. Cancer. 115:4576–4585
Hall CA, Wang R, Miao J, Oliva E, Shen X, Wheeler T, Hilsenbeck SG, Orsulic S, Goode S (2010) Hippo pathway effector yap is an ovarian cancer oncogene. Cancer Res 70:8517–8525
Zhang C, Liang K, Zhou G, Zhang Q, Li J (2014) Expression of hippo pathway in colorectal cancer. Saudi J Gastroenterol 20:188
Zhou G-X, Li X-Y, Zhang Q, Zhao K, Zhang C-P, Xue C-H, Yang K, Tian ZB (2013) Effects of the hippo signaling pathway in human gastric cancer. Asian Pac J Cancer Prev 14:5199–5205
Ge L, Smail M, Meng W, Shyr Y, Ye F, Fan K-H, Li X, Zhou HM, Bhowmick NA Yes-associated protein expression in head and neck squamous cell carcinoma nodal metastasis. Ramqvist T, editor. PLoS One 2011;6:e27529
Pei T, Li Y, Wang J, Wang H, Liang Y, Shi H et al (2015) YAP is a critical oncogene in human cholangiocarcinoma. Oncotarget. 6:17206–17220
Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, Jacobsen A, Byrne CJ, Heuer ML, Larsson E, Antipin Y, Reva B, Goldberg AP, Sander C, Schultz N (2012) The cBio Cancer genomics portal: an open platform for exploring multidimensional Cancer genomics data. Cancer Discov 2(5):401–404
Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO et al (2013) Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal 6:pl1
Bao Y, Hata Y, Ikeda M, Withanage K (2011) Mammalian hippo pathway: from development to cancer and beyond. J Biochem 149:361–379
Zhang L, Yang S, Chen X, Stauffer S, Yu F, Lele SM et al (2015) The hippo pathway effector YAP regulates motility , invasion , and castration-resistant growth of. Prostate Cancer Cells 35:1350–1362
Kuser-Abali G, Alptekin A, Lewis M, Garraway IP, Cinar B (2015) YAP1 and AR interactions contribute to the switch from androgen-dependent to castration-resistant growth in prostate cancer. Nat Commun 6:8126
Sheng X, Bin LW, Wang DL, Chen KH, Cao JJ, Luo Z et al (2015) YAP is closely correlated with castration-resistant prostate cancer, and downregulation of YAP reduces proliferation and induces apoptosis of PC-3 cells. Mol Med Rep 12:4867–4876
Gu S, Chen K, Yin M, Wu Z, Wu Y (2016) Proteomic profiling of isogenic primary and metastatic medulloblastoma cell lines reveals differential expression of key metastatic factors. J Proteome 160:55–63
Lee HJ, Diaz MF, Price KM, Ozuna JA, Zhang S, Sevick-muraca EM, et al. Fluid shear stress activates YAP1 to promote cancer cell motility. 2017; 8:14122
Haemmerle M, Taylor ML, Gutschner T, Pradeep S, Cho MS, Sheng J, Lyons YM, Nagaraja AS, Dood RL, Wen Y, Mangala LS, Hansen JM, Rupaimoole R, Gharpure KM, Rodriguez-Aguayo C, Yim SY, Lee JS, Ivan C, Hu W, Lopez-Berestein G, Wong ST, Karlan BY, Levine DA, Liu J, Afshar-Kharghan V, Sood AK (2017) Platelets reduce anoikis and promote metastasis by activating YAP1 signaling. Nat Commun 8:310
Chai J, Xu S, Guo F (2017) TEAD1 mediates the oncogenic activities of hippo-YAP1 signaling in osteosarcoma. Biochem Biophys Res Commun 488:297–302
Grannas K, Arngården L, Lönn P, Mazurkiewicz M, Blokzijl A, Zieba A et al (2015) Crosstalk between hippo and TGFβ: subcellular localization of YAP/TAZ/Smad complexes. J Mol Biol 427:3407–3415
Ferrigno O, Lallemand F, Verrecchia F, L’Hoste S, Camonis J, Atfi A et al (2002) Yes-associated protein (YAP65) interacts with Smad7 and potentiates its inhibitory activity against TGF-beta/Smad signaling. Oncogene 21:4879–4884
Vitolo MI, Anglin IE, Mahoney WM, Renoud KJ, Gartenhaus RB, Bachman KE, Passaniti A (2007) The RUNX2 transcription factor cooperates with the YES-associated protein, YAP65, to promote cell transformation. Cancer Biol Ther 6:856–863
Omerovic J, Puggioni EM, Napoletano S, Visco V, Fraioli R, Frati L et al (2004) Ligand-regulated association of ErbB-4 to the transcriptional co-activator YAP65 controls transcription at the nuclear level. Exp Cell Res 294:469–479
Hoang DT, Iczkowski KA, Kilari D, See W, Nevalainen MT (2017) Androgen receptor-dependent and -independent mechanisms driving prostate cancer progression: opportunities for therapeutic targeting from multiple angles. Oncotarget 8:3724–3745
Shiota M, Yokomizo A, Fujimoto N, Naito S (2011) Androgen receptor cofactors in prostate Cancer: potential therapeutic targets of castration-resistant prostate Cancer. Curr Cancer Drug Targets 11:870–881
Nguyen, Liem T.l. Nguyen LT, Tretiakova MS, Silvis MR et al. EA the YTP and I the D of A-RPTCC 2015;27(6):797–808. doi:10. 1016/j. ccell. 2015. 05. 005.
Tretiakova MS, Silvis MR, Lucas J, Klezovitch O, Coleman I et al (2015) ERG Activates the YAP1 Transcriptional Program and Induces the Development of Age-Related Prostate Tumors. Cancer Cell 27:797–808
Lehmann W, Mossmann D, Kleemann J, Mock K, Meisinger C, Brummer T, Herr R, Brabletz S, Stemmler MP, Brabletz T ZEB1 turns into a transcriptional activator by interacting with YAP1 in aggressive cancer types. Nat Commun ; 2016;7:10498
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This work is financially supported by the The Scientific and Technological Research Council of Turkey (TUBITAK) (P.No:114S419) and Istanbul Medeniyet University Scientific Research Grants (FBA-2014-293).
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Collak, F.K., Demir, U. & Sagir, F. YAP1 Is Involved in Tumorigenic Properties of Prostate Cancer Cells. Pathol. Oncol. Res. 26, 867–876 (2020). https://doi.org/10.1007/s12253-019-00634-z
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DOI: https://doi.org/10.1007/s12253-019-00634-z