Abstract
Prostate cancer (PC) is a major health and economic problem in industrialized countries, yet our understanding of the molecular mechanisms of PC progression and drug response remains limited. Accumulating evidence showed that certain E3 ubiquitin ligases such as SIAH2, RNF7, and SPOP play important roles in PC development and progression. However, the roles and mechanisms of other E3s in PC progression remain largely unexplored. Through an integration analysis of clinical genomic and transcriptomic profiles of PC tumors, this study identified UBR5 as a top PC-relevant E3 ubiquitin ligase whose expression levels are strongly associated with PC progression and aggressiveness. BoxCar and shotgun proteomic analyses of control and UBR5-knockdown PC3 cells complementarily identified 75 UBR5-regulated proteins. Bioinformatic analysis suggested that the 75 proteins form four molecular networks centered around FANCD2, PAF1, YY1, and LAMB3 via direct protein-protein interactions. Experimental analyses demonstrated that UBR5 associates with and downregulates two key DNA damage repair proteins (XRCC3 and FANCD2) and confers PC cell sensitivity to olaparib, a PARP inhibitor in clinical use for cancer therapy. This study represents the first application of BoxCar in PC research, provides new insights into the molecular functions of UBR5 in PC, and suggests that PC patients with UBR5-high tumors may potentially benefit from PARP inhibitor treatment.