Human Cancer Biology 14-3-3z, a Novel Androgen-Responsive Gene, Is Upregulated in Prostate Cancer and Promotes Prostate Cancer Cell Proliferation and Survival

Purpose:Androgen receptor is an essential transcriptional factor that contributes to the development and progressionof prostate cancer. In this study,we investigated the androgen regulation and functional analysis of 14-3-3z in prostate cancer. Experimental Design:Using chromatin immunoprecipitation (ChIP) combined with DNAmicroarray (ChIP-chip) analysis in LNCaP cells, we identified a functional androgen receptor–binding site in the downstream region of the 14-3-3z gene. Androgen regulation was examined by quantitative reverse transcription PCR and Western blot analysis. Prostate cancer cells stably expressing 14-3-3z and siRNA knockdown were used for functional analyses. We further examined 14-3-3z expression in clinical samples of prostate cancer by immunohistochemistry and quantitative reverse transcription PCR. Results:Androgen-dependent upregulation of 14-3-3zwas validated at themRNAandprotein levels. The 14-3-3z 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. 14-3-3z expressionwas associated with androgen receptor transcriptional activity and prostate-specific antigen (PSA) mRNA expression. Immunoprecipitation indicated that 14-3-3z was associated with androgen receptor in the nucleus. Clinicopathologic studies further support the relevance of 14-3-3z in prostate cancers, as its higher expression is associated with malignancy and lymph node metastasis. Conclusions: 14-3-3z is a novel androgen-responsive gene that activates proliferation, cell survival, and androgen receptor transcriptional activity. 14-3-3zmay facilitate the progression of prostate cancer. Clin Cancer Res; 18(20); 5617–27. 2012 AACR.