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BoxCar and shotgun proteomic analyses reveal molecular networks regulated by UBR5 in prostate cancer
Yiwu Yan1, Bo Zhou1, Yeon-Joo Lee1
1Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
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.
Insights
This study identifies UBR5 as a key E3 ubiquitin ligase in prostate cancer (PC) progression. UBR5-high tumors may respond better to PARP inhibitor therapy, offering new treatment avenues.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Prostate cancer (PC) poses significant health and economic challenges globally.
- Understanding PC molecular mechanisms, including E3 ubiquitin ligases, is crucial for improved treatments.
- Previous studies highlighted SIAH2, RNF7, and SPOP, but other E3 ligases in PC remain understudied.
Purpose of the Study:
- To identify novel E3 ubiquitin ligases involved in prostate cancer (PC) progression.
- To elucidate the molecular mechanisms and clinical relevance of UBR5 in PC.
- To explore the potential of UBR5 as a predictive biomarker for PARP inhibitor response.
Main Methods:
- Integrated analysis of clinical genomic and transcriptomic profiles of PC tumors.
- BoxCar and shotgun proteomic analyses in UBR5-knockdown PC3 cells.
- Bioinformatic network analysis and experimental validation of protein interactions and functions.
Main Results:
- UBR5 was identified as a top PC-relevant E3 ubiquitin ligase, with expression linked to PC progression and aggressiveness.
- Proteomic analysis identified 75 UBR5-regulated proteins, forming networks around FANCD2, PAF1, YY1, and LAMB3.
- UBR5 downregulates DNA damage repair proteins XRCC3 and FANCD2, conferring sensitivity to olaparib (a PARP inhibitor).
Conclusions:
- UBR5 plays a significant role in prostate cancer progression and aggressiveness.
- UBR5 activity impacts DNA damage repair pathways and sensitivity to PARP inhibitors.
- UBR5 expression may predict treatment response to olaparib in PC patients.
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