14-3-3ζ, 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 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.