title: The hippo pathway effector YAP regulates motility, invasion, and castration-resistant growth of prostate cancer cells.
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: 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.
authors: Lin
authors: L
authors: Zhang
authors: 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.
authors: Shuping
authors: S
authors: Yang
authors: 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.
authors: Xingcheng
authors: X
authors: Chen
authors: 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.
authors: Seth
authors: S
authors: Stauffer
authors: Department of Biostatistics, School of Public Health, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors: Fang
authors: F
authors: Yu
authors: Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors: Subodh M
authors: SM
authors: Lele
authors: Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors: Kai
authors: K
authors: Fu
authors: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors: Kaustubh
authors: K
authors: Datta
authors: Holland Computing Center, University of Nebraska-Lincoln, Lincoln, Nebraska, USA.
authors: Nicholas
authors: N
authors: Palermo
authors: Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors: Yuanhong
authors: Y
authors: Chen
authors: 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.
authors: Jixin
authors: J
authors: Dong
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000728:Androgens / Q000378:metabolism; D000818:Animals; D002369:Castration; D002465:Cell Movement; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D000090683:Hippo Signaling Pathway; D006801:Humans; D020935:MAP Kinase Signaling System; D008297:Male; D016513:Mice, SCID; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D011467:Prostate / Q000378:metabolism / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors; D015854:Up-Regulation; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000728:Androgens; D010750:Phosphoproteins; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D017346:Protein Serine-Threonine Kinases
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