After long-term androgen deprivation therapy, 25–30% prostate cancer (PCa) acquires an aggressive neuroendocrine (NE) phenotype. Dysregulation of YAP1, a key transcription coactivator of the Hippo pathway, has been related to cancer progression. However, its role in neuroendocrine prostate cancer (NEPC) has not been assessed.
Immunohistochemistry and bioinformatics analysis were conducted to evaluate YAP1 expression levels during PCa initiation and progression.
YAP1 expression was present in the basal epithelial cells in benign prostatic tissues, lost in low-grade PCa, but elevated in high-grade prostate adenocarcinomas. Interestingly, the expression of YAP1 was reduced/lost in both human and mouse NEPC.
The expression of YAP1 is elevated in high-grade prostate adenocarcinomas but lost in NEPC.
Subscribe to Journal
Get full journal access for 1 year
only $99.75 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Debes JD, Tindall DJ. Mechanisms of androgen-refractory prostate cancer. N. Engl J Med. 2004;351:1488–90.
Dehm SM, Tindall DJ. Molecular regulation of androgen action in prostate cancer. J Cell Biochem. 2006;99:333–44.
Beltran H, Tomlins S, Aparicio A, Arora V, Rickman D, Ayala G, et al. Aggressive variants of castration-resistant prostate cancer. Clin Cancer Res. 2014;20:2846–50.
Ma S, Meng Z, Chen R, Guan KL. The Hippo pathway: biology and pathophysiology. Annu Rev Biochem. 2019;88:577–604.
Azzolin L, Panciera T, Soligo S, Enzo E, Bicciato S, Dupont S, et al. YAP/TAZ incorporation in the β-catenin destruction complex orchestrates the Wnt response. Cell. 2014;158:157–70.
Varelas X, Miller BW, Sopko R, Song S, Gregorieff A, Fellouse FA, et al. The Hippo pathway regulates Wnt/beta-catenin signaling. Dev. Cell. 2010;18:579–91.
Yu FX, Zhao B, Guan KL. Hippo pathway in organ size control, tissue homeostasis, and cancer. Cell. 2015;163:811–28.
Ito T, Matsubara D, Tanaka I, Makiya K, Tanei ZI, Kumagai Y, et al. Loss of YAP1 defines neuroendocrine differentiation of lung tumors. Cancer Sci. 2016;107:1527–38.
Zhang L, Yang S, Chen X, Stauffer S, Yu F, Lele SM, et al. The hippo pathway effector YAP regulates motility, invasion, and castration-resistant growth of prostate cancer cells. Mol Cell Biol. 2015;35:1350–62.
Kuser-Abali G, Alptekin A, Lewis M, Garraway IP, Cinar B. YAP1 and AR interactions contribute to the switch from androgen-dependent to castration-resistant growth in prostate cancer. Nat Commun. 2015;6:8126.
Connelly ZM, Yang S, Chen F, Yeh Y, Khater N, Jin R, et al. Foxa2 activates the transcription of androgen receptor target genes in castrate resistant prostatic tumors. Am J Clin Exp Urol. 2018;6:172–81.
Team R. RStudio: Integrated Development Environment for R. Boston, MA: RStudio, Inc.; 2015.
Ge SX, Jung D, Yao R. ShinyGO: a graphical enrichment tool for animals and plants. Bioinformatics. 2019. [Epub ahead of print].
Veeman MT, Slusarski DC, Kaykas A, Louie SH, Moon RT. Zebrafish prickle, a modulator of noncanonical Wnt/Fz signaling, regulates gastrulation movements. Curr Biol. 2003;13:680–5.
Greenberg NM, DeMayo F, Finegold MJ, Medina D, Tilley WD, Aspinall JO, et al. Prostate cancer in a transgenic mouse. Proc Natl Acad Sci USA. 1995;92:3439–43.
Kasper S, Sheppard PC, Yan Y, Pettigrew N, Borowsky AD, Prins GS, et al. Development, progression, and androgen-dependence of prostate tumors in probasin-large T antigen transgenic mice: a model for prostate cancer. Lab Invest. 1998;78:i–xv.
Huss WJ, Gray DR, Tavakoli K, Marmillion ME, Durham LE, Johnson MA, et al. Origin of androgen-insensitive poorly differentiated tumors in the transgenic adenocarcinoma of mouse prostate model. Neoplasia. 2007;9:938–50.
Masumori N, Thomas TZ, Chaurand P, Case T, Paul M, Kasper S, et al. A probasin-large T antigen transgenic mouse line develops prostate adenocarcinoma and neuroendocrine carcinoma with metastatic potential. Cancer Res. 2001;61:2239–49.
Masumori N, Tsuchiya K, Tu WH, Lee C, Kasper S, Tsukamoto T, et al. An allograft model of androgen independent prostatic neuroendocrine carcinoma derived from a large probasin promoter-T antigen transgenic mouse line. J Urol. 2004;171:439–42.
Beltran H, Prandi D, Mosquera JM, Benelli M, Puca L, Cyrta J, et al. Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer. Nat Med. 2016;22:298–305.
Cheng S, Yu X. Bioinformatics analyses of publicly available NEPCa datasets. Am J Clin Exp Urol. 2019;7:327–40.
Barretina J, Caponigro G, Stransky N, Venkatesan K, Margolin AA, Kim S, et al. The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature. 2012;483:603–7.
Yang X, Chen MW, Terry S, Vacherot F, Chopin DK, Bemis DL, et al. A human- and male-specific protocadherin that acts through the wnt signaling pathway to induce neuroendocrine transdifferentiation of prostate cancer cells. Cancer Res. 2005;65:5263–71.
Yu X, Wang Y, DeGraff DJ, Wills ML, Matusik RJ. Wnt/beta-catenin activation promotes prostate tumor progression in a mouse model. Oncogene. 2011;30:1868–79.
Nishikawa E, Osada H, Okazaki Y, Arima C, Tomida S, Tatematsu Y, et al. miR-375 is activated by ASH1 and inhibits YAP1 in a lineage-dependent manner in lung cancer. Cancer Res. 2011;71:6165–73.
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;15:1752–9.
Liu CY, Yu T, Huang Y, Cui L, Hong W. ETS (E26 transformation-specific) up-regulation of the transcriptional co-activator TAZ promotes cell migration and metastasis in prostate cancer. J Biol Chem. 2017;292:9420–30.
Feng J, Ren P, Gou J, Li Z. Prognostic significance of TAZ expression in various cancers: a meta-analysis. OncoTargets Ther. 2016;9:5235–44.
Sun Z, Xu R, Li X, Ren W, Ou C, Wang Q, et al. Prognostic value of yes-associated protein 1 (YAP1) in various cancers: a meta-analysis. PloS one. 2015;10:e0135119.
Jiang N, Ke B, Hjort-Jensen K, Iglesias-Gato D, Wang Z, Chang P, et al. YAP1 regulates prostate cancer stem cell-like characteristics to promote castration resistant growth. Oncotarget. 2017;8:115054–67.
Horie M, Saito A, Ohshima M, Suzuki HI, Nagase T. YAP and TAZ modulate cell phenotype in a subset of small cell lung cancer. Cancer Sci. 2016;107:1755–66.
Imajo M, Miyatake K, Limura A, Miyamoto A, Nishida E. A molecular mechanism that links Hippo signalling to the inhibition of Wnt/beta-catenin signalling. EMBO J. 2012;31:1109–22.
Barry ER, Morikawa T, Butler BL, Shrestha K, de la Rosa R, Yan KS, et al. Restriction of intestinal stem cell expansion and the regenerative response by YAP. Nature. 2013;493:106–10.
Plouffe SW, Lin KC, Moore JL 3rd, Tan FE, Ma S, Ye Z, et al. The Hippo pathway effector proteins YAP and TAZ have both distinct and overlapping functions in the cell. J Biol Chem. 2018;293:11230–40.
Callus BA, Finch-Edmondson ML, Fletcher S, Wilton SD. YAPping about and not forgetting TAZ. FEBS Lett. 2019;593:253–76.
We thank Dr Robert Matusik at Vanderbilt University for providing tissues of LADY mice and advice on this research. This research was supported by NIH R03 CA212567, R01 CA226285, U54 GM104940, DOD W81XWH-12-1-0212, and LSUHSC FWCC and Office of Research funding to XY.
Conflict of interest
The authors declare that they have no conflict of interest.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Cheng, S., Prieto-Dominguez, N., Yang, S. et al. The expression of YAP1 is increased in high-grade prostatic adenocarcinoma but is reduced in neuroendocrine prostate cancer. Prostate Cancer Prostatic Dis 23, 661–669 (2020). https://doi.org/10.1038/s41391-020-0229-z
Neuroendocrine prostate cancer has distinctive, non-prostatic HOX code that is represented by the loss of HOXB13 expression
Scientific Reports (2021)
Re: The expression of YAP1 is increased in high-grade prostatic adenocarcinoma but is reduced in neuroendocrine prostate cancer
Prostate Cancer and Prostatic Diseases (2021)
Resistance to androgen receptor signaling inhibition does not necessitate development of neuroendocrine prostate cancer
JCI Insight (2021)
The Prostate (2021)