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The hippo pathway effector YAP regulates motility, invasion, and castration-resistant growth of prostate cancer cells.
Mol Cell Biol. 2015 Apr; 35(8):1350-62.MC

Abstract

Yes-associated protein (YAP) is an effector of the Hippo tumor suppressor pathway. The functional significance of YAP in prostate cancer has remained elusive. In this study, we first show that enhanced expression of YAP is able to transform immortalized prostate epithelial cells and promote migration and invasion in both immortalized and cancerous prostate cells. We found that YAP mRNA was upregulated in androgen-insensitive prostate cancer cells (LNCaP-C81 and LNCaP-C4-2 cells) compared to the level in androgen-sensitive LNCaP cells. Importantly, ectopic expression of YAP activated androgen receptor signaling and was sufficient to promote LNCaP cells from an androgen-sensitive state to an androgen-insensitive state in vitro, and YAP conferred castration resistance in vivo. Accordingly, YAP knockdown greatly reduced the rates of migration and invasion of LNCaP-C4-2 cells and under androgen deprivation conditions largely blocked cell division in LNCaP-C4-2 cells. Mechanistically, we found that extracellular signal-regulated kinase-ribosomal s6 kinase signaling was downstream of YAP for cell survival, migration, and invasion in androgen-insensitive cells. Finally, immunohistochemistry showed significant upregulation and hyperactivation of YAP in castration-resistant prostate tumors compared to their levels in hormone-responsive prostate tumors. Together, our results identify YAP to be a novel regulator in prostate cancer cell motility, invasion, and castration-resistant growth and as a potential therapeutic target for metastatic castration-resistant prostate cancer (CRPC).

Authors+Show Affiliations

Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska, USA Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska, USA.Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska, USA Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska, USA Department of Oncology, Shandong Provincial Hospital affiliated with Shandong University, Jinan, Shandong, People's Republic of China.Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska, USA Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska, USA.Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska, USA Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska, USA.Department of Biostatistics, School of Public Health, University of Nebraska Medical Center, Omaha, Nebraska, USA.Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska, USA.Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska, USA.Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, USA.Holland Computing Center, University of Nebraska-Lincoln, Lincoln, Nebraska, USA.Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska, USA.Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska, USA dongj@unmc.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

25645929

Citation

Zhang, Lin, et al. "The Hippo Pathway Effector YAP Regulates Motility, Invasion, and Castration-resistant Growth of Prostate Cancer Cells." Molecular and Cellular Biology, vol. 35, no. 8, 2015, pp. 1350-62.
Zhang L, Yang S, Chen X, et al. The hippo pathway effector YAP regulates motility, invasion, and castration-resistant growth of prostate cancer cells. Mol Cell Biol. 2015;35(8):1350-62.
Zhang, L., Yang, S., Chen, X., Stauffer, S., Yu, F., Lele, S. M., Fu, K., Datta, K., Palermo, N., Chen, Y., & Dong, J. (2015). The hippo pathway effector YAP regulates motility, invasion, and castration-resistant growth of prostate cancer cells. Molecular and Cellular Biology, 35(8), 1350-62. https://doi.org/10.1128/MCB.00102-15
Zhang L, et al. The Hippo Pathway Effector YAP Regulates Motility, Invasion, and Castration-resistant Growth of Prostate Cancer Cells. Mol Cell Biol. 2015;35(8):1350-62. PubMed PMID: 25645929.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The hippo pathway effector YAP regulates motility, invasion, and castration-resistant growth of prostate cancer cells. AU - Zhang,Lin, AU - Yang,Shuping, AU - Chen,Xingcheng, AU - Stauffer,Seth, AU - Yu,Fang, AU - Lele,Subodh M, AU - Fu,Kai, AU - Datta,Kaustubh, AU - Palermo,Nicholas, AU - Chen,Yuanhong, AU - Dong,Jixin, Y1 - 2015/02/02/ PY - 2015/2/4/entrez PY - 2015/2/4/pubmed PY - 2015/6/3/medline SP - 1350 EP - 62 JF - Molecular and cellular biology JO - Mol. Cell. Biol. VL - 35 IS - 8 N2 - Yes-associated protein (YAP) is an effector of the Hippo tumor suppressor pathway. The functional significance of YAP in prostate cancer has remained elusive. In this study, we first show that enhanced expression of YAP is able to transform immortalized prostate epithelial cells and promote migration and invasion in both immortalized and cancerous prostate cells. We found that YAP mRNA was upregulated in androgen-insensitive prostate cancer cells (LNCaP-C81 and LNCaP-C4-2 cells) compared to the level in androgen-sensitive LNCaP cells. Importantly, ectopic expression of YAP activated androgen receptor signaling and was sufficient to promote LNCaP cells from an androgen-sensitive state to an androgen-insensitive state in vitro, and YAP conferred castration resistance in vivo. Accordingly, YAP knockdown greatly reduced the rates of migration and invasion of LNCaP-C4-2 cells and under androgen deprivation conditions largely blocked cell division in LNCaP-C4-2 cells. Mechanistically, we found that extracellular signal-regulated kinase-ribosomal s6 kinase signaling was downstream of YAP for cell survival, migration, and invasion in androgen-insensitive cells. Finally, immunohistochemistry showed significant upregulation and hyperactivation of YAP in castration-resistant prostate tumors compared to their levels in hormone-responsive prostate tumors. Together, our results identify YAP to be a novel regulator in prostate cancer cell motility, invasion, and castration-resistant growth and as a potential therapeutic target for metastatic castration-resistant prostate cancer (CRPC). SN - 1098-5549 UR - https://www.unboundmedicine.com/medline/citation/25645929/The_hippo_pathway_effector_YAP_regulates_motility_invasion_and_castration_resistant_growth_of_prostate_cancer_cells_ L2 - http://mcb.asm.org/cgi/pmidlookup?view=long&pmid=25645929 DB - PRIME DP - Unbound Medicine ER -