AbstractBACKGROUNDGlycoprotein transmembrane nmb (GPNMB) gene was originally identified in osteoblasts and belongs to the pmel‐17/nmb family. The function or regulation of GPNMB in the human prostate remains unknown.METHODSThe expression of GPNMB in prostate carcinoma cells were determined by real‐time reverse transcription‐polymerase chain reaction (RT‐qPCR) and immunoblot assays. Effects of ectopic GPNMB overexpression on cell proliferation, invasion, and tumorigenesis were determined by 3H‐thymidine incorporation, matrigel invasion, soft agar cloning assays, and murine xenograft study. Effects of GPNMB, p53, and androgen on target gene were assessed using RT‐PCR, immunoblotting, and transient gene expression assays.RESULTSIn vitro analysis using several prostate cell lines suggested that expression of GPNMB may be relevant to the extent of neoplasia. Ectopic overexpression of GPNMB significantly attenuated cell proliferation and invasion and exerted antitumorigenic activity on PC‐3 cells in vitro and in vivo. GPNMB overexpression induced the gene expressions of N‐myc downstream regulated gene 1 (Ndrg1) and maspin in PC‐3 cells. Doxorubicin treatment or transient overexpression of p53 increased GPNMB expression. Androgen (R1881) treatment has a divergent effect on gene expression of prostate‐specific antigen (PSA) and GPNMB in LNCaP cells. Androgen treatment enhanced cell proliferation but downregulated GPNMB protein expression in stably overexpressed androgen receptor (AR) CA‐HPV‐10 cells.CONCLUSIONSTogether these results suggest that GPNMB gene is a p53‐ and androgen‐dysregulated gene and should be regarded as an anti‐tumor gene for prostate cancer. The enhancement of Ndrg1 and maspin gene expressions may account for the anti‐proliferative and anti‐invasive function of GPNMB in PC‐3 cells. Prostate 72:1431–1442, 2012. © 2012 Wiley Periodicals, Inc.