PURPOSE: Androgen receptor is an essential transcriptional factor that contributes to the development and progression of prostate cancer.
In this study, we investigated the androgen regulation and functional analysis of 14-3-3ζ in prostate cancer.
EXPERIMENTAL DESIGN: Using chromatin immunoprecipitation (ChIP) combined with DNA microarray (ChIP-chip) analysis in LNCaP cells, we identified a functional androgen receptor-binding site in the downstream region of the 14-3-3ζ gene. Androgen regulation was examined by quantitative reverse transcription PCR and Western blot analysis. Prostate cancer cells stably expressing 14-3-3ζ and siRNA knockdown were used for functional analyses. We further examined 14-3-3ζ expression in clinical samples of prostate cancer by immunohistochemistry and quantitative reverse transcription PCR.
RESULTS: Androgen-dependent upregulation of 14-3-3ζ was validated at the mRNA and protein levels. The 14-3-3ζ gene is favorable for cancer-cell survival, as its ectopic expression in LNCaP cells contributes to cell proliferation and the acquired resistance to etoposide-induced apoptosis. 14-3-3ζ expression was associated with androgen receptor transcriptional activity and prostate-specific antigen (PSA) mRNA expression. Immunoprecipitation indicated that 14-3-3ζ was associated with androgen receptor in the nucleus. Clinicopathologic studies further support the relevance of 14-3-3ζ in prostate cancers, as its higher expression is associated with malignancy and lymph node metastasis.
CONCLUSIONS: 14-3-3ζ is a novel androgen-responsive gene that activates proliferation, cell survival, and androgen receptor transcriptional activity. 14-3-3ζ may facilitate the progression of prostate cancer.
Written by:
Murata T, Takayama K, Urano T, Fujimura T, Ashikari D, Obinata D, Horie-Inoue K, Takahashi S, Ouchi Y, Homma Y, Inoue S. Are you the author?
Departments of Anti-Aging Medicine, Urology, and Geriatric Medicine, Graduate School of Medicine, The University of Tokyo; Department of Urology, School of Medicine, Nihon University, Tokyo; and Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical University, Saitama, Japan.
Reference: Clin Cancer Res. 2012 Oct 15;18(20):5617-27.
doi: 10.1158/1078-0432.CCR-12-0281
PubMed Abstract
PMID: 22904106
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