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DC‐SCRIPT: AR and VDR regulator lost upon transformation of prostate epithelial cells
Author(s) -
Ansems Marleen,
Karthaus Nina,
Hontelez Saartje,
Aalders Tilly,
Looman Maaike W.,
Verhaegh Gerald W.,
Schalken Jack A.,
Adema Gosse J.
Publication year - 2012
Publication title -
the prostate
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.295
H-Index - 123
eISSN - 1097-0045
pISSN - 0270-4137
DOI - 10.1002/pros.22522
Subject(s) - prostate cancer , prostate , calcitriol receptor , cancer research , androgen receptor , biology , dihydrotestosterone , pca3 , immunohistochemistry , androgen , receptor , medicine , endocrinology , cancer , hormone
BACKGROUND Nuclear receptors (NR), including the Androgen Receptor (AR) and the Vitamin D Receptor (VDR), play an important role in prostate cancer etiology. We recently found that DC‐SCRIPT is a prognostic marker in breast cancer and a unique NR coregulator differentially regulating different classes of NRs. Here we investigated the importance of DC‐SCRIPT in prostate cancer. METHODS DC‐SCRIPT mRNA expression was measured by qPCR. Immunohistochemistry was used to detect DC‐SCRIPT protein expression. The functional effects of DC‐SCRIPT on the transcriptional activity of AR and VDR were assessed by luciferase reporter assays and qPCR assays on well‐known AR and VDR target genes. RESULTS DC‐SCRIPT mRNA was higher in normal than in corresponding malignant prostate tissue but could not be related to disease stage. DC‐SCRIPT protein was found in morphologically normal prostate glands and in infiltrating immune cells. Strikingly, DC‐SCRIPT protein expression was absent in malignant prostate epithelial tissue and prostate carcinoma cell lines. DC‐SCRIPT protein expression appears to be lost prior to the basal cell marker HMW cytokeratin used in prostate carcinoma diagnostics. In addition, our data demonstrated that DC‐SCRIPT repressed transcription mediated by wild‐type and mutated AR while enhancing VDR mediated transcription. In addition, transient expression of DC‐SCRIPT expression in prostate carcinoma cells strongly repressed cell growth. CONCLUSIONS DC‐SCRIPT is a key regulator of nuclear receptors AR and VDR that play an opposite role in prostate cancer etiology and loss of DC‐SCRIPT may be involved in the onset of prostate cancer. Prostate 72:1708–1717, 2012. © 2012 Wiley Periodicals, Inc.