The hippo pathway effector YAP regulates motility, invasion, and castration-resistant growth of prostate cancer cells

Lin Zhang, Shuping Yang, Xingcheng Chen, Seth Stauffer, Fang Yu, Subodh M Lele, Kai Fu, Kaustubh Datta, Nicholas Palermo, Yuanhong Chen, Jixin Dong

Research output: Contribution to journalArticle

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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).

Original languageEnglish (US)
Pages (from-to)1350-1362
Number of pages13
JournalMolecular and cellular biology
Volume35
Issue number8
DOIs
StatePublished - Jan 1 2015

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Molecular Motor Proteins
Castration
Prostatic Neoplasms
Androgens
Growth
Proteins
Prostate
Cell Movement
Ribosomal Protein S6 Kinases
Neoplasms
Extracellular Signal-Regulated MAP Kinases
Androgen Receptors
Cell Division
Cell Survival
Up-Regulation

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

The hippo pathway effector YAP regulates motility, invasion, and castration-resistant growth of prostate cancer cells. / Zhang, Lin; Yang, Shuping; Chen, Xingcheng; Stauffer, Seth; Yu, Fang; Lele, Subodh M; Fu, Kai; Datta, Kaustubh; Palermo, Nicholas; Chen, Yuanhong; Dong, Jixin.

In: Molecular and cellular biology, Vol. 35, No. 8, 01.01.2015, p. 1350-1362.

Research output: Contribution to journalArticle

Zhang, Lin ; Yang, Shuping ; Chen, Xingcheng ; Stauffer, Seth ; Yu, Fang ; Lele, Subodh M ; Fu, Kai ; Datta, Kaustubh ; Palermo, Nicholas ; Chen, Yuanhong ; Dong, Jixin. / The hippo pathway effector YAP regulates motility, invasion, and castration-resistant growth of prostate cancer cells. In: Molecular and cellular biology. 2015 ; Vol. 35, No. 8. pp. 1350-1362.
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