부산대학교 도서관

Recent evidence support that the c- J un a ctivation domain- b inding protein 1 (JAB1)/COPS5 has an oncogenic function in various tissues. We show that JAB1 amplification in human prostate cancer (PCa) correlates with reduced overall survival and disease-free progression. Immunohistochemical staining shows enhanced expression of JAB1 in the cytoplasmic compartment of PCa cells compared to the normal prostate epithelium, indicating the activity/function of JAB1 is altered in PCa. To test the function of JAB1 in PCa, we efficiently silenced JAB1 expression using four unique shRNAs in three PCa cell lines (LNCaP, C4-2, and PC-3) and an immortalized prostate epithelial cell line, RWPE-1. Our data clearly show that silencing JAB1 robustly suppresses the growth of PCa cells, but not RWPE-1 cells, suggesting that PCa cells become addicted to JAB1. To study the potential mechanism by which JAB1 controls PCa growth, we profiled gene expression changes by whole transcriptome microarray analysis of C4-2 cells silenced for JAB1 using a pool of 3 shRNAs compared to scrambled shRNA control. We identified 1268 gene changes ≥1.5 fold by silencing JAB1 in C4-2. Western blot confirmation and bioinformatics pathway analyses support that PCa cells become addicted to JAB1 through controlling the following signaling pathways: cell cycle, p53 signaling, DNA replication, TGF-β/BMP, MAPK, TNF, and steroid hormone biosynthesis. We propose that UGT2B28, UGT2B10, UGT2B11, Skp2, EZH2, MDM2, BIRC5 (Survivin), UBE2C, and Smads 1/5/8, which are all associated with the abovementioned key oncogenic pathways, may play critical roles in the putative oncogenic function of JAB1 in PCa. • The JAB1 gene is highly amplified in human prostate cancer (PCa). • Amplification of JAB1 in human PCa is a predictive marker of poor overall survival. • Silencing of JAB1 in human PCa cell lines is cytostatic and causes their death. • Silencing JAB1 in a non-malignant prostate line was not cytostatic/cytotoxic. • Transcriptome and Western analyses support JAB1 as a central controller of PCa. [ABSTRACT FROM AUTHOR]