14-3-3ζ, a novel androgen-responsive gene, is upregulated in prostate cancer and promotes prostate cancer cell proliferation and survival.
OBJECTIVE
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.


METHODS
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.
Department of Anti-Aging Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Taro
T
Murata
Ken-ichi
K
Takayama
Tomohiko
T
Urano
Tetsuya
T
Fujimura
Daisaku
D
Ashikari
Daisuke
D
Obinata
Kuniko
K
Horie-Inoue
Satoru
S
Takahashi
Yasuyoshi
Y
Ouchi
Yukio
Y
Homma
Satoshi
S
Inoue
D048948:14-3-3 Proteins / Q000235:genetics / Q000378:metabolism; D000728:Androgens / Q000378:metabolism; D017209:Apoptosis; D001665:Binding Sites; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D009376:Neoplasms, Hormone-Dependent / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism; D011485:Protein Binding; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
D048948:14-3-3 Proteins; C410798:AR protein, human; D000728:Androgens; D011944:Receptors, Androgen; C572235:YWHAZ protein, human