Regulation of PARP Activity by Ubiquitin E3 Ligase RNF6 in Prostate Cancer
Abstract
Poly(ADP-ribose) polymerase (PARP) inhibitors act through synthetic lethality with mutations in DNA repair genes and are approved for treatment of cancers with BRCA1/2 mutation, including prostate cancer. The effectiveness of current targeted therapy for CRPC is limited by the lack of reliable markers to identify the patients who most likely benefit from PARP inhibitors (PARPi) and their combination therapy. Efficacy of PARPi as a monotherapy is limited to a small subset of prostate cancer patients. Identification of new PARP regulators relevant to PCa is critical for improving the efficacy of current PARPi and developing new effective combination therapy. This is a proof-of-concept study to investigate a novel functional interaction between PARP1 and RNF6 by characterization of RNF6- induced ubiquitination of PARP1 and test whether RNF6 modulates sensitivity to PARPi in prostate cancer cells. The effects of RNF6-induced ubiquitination on PARP1 polymerase activity, gene transcription regulation, chromatin association, and protein partner recruitment and sensitivity to PARPi will be examined in PCa cells. A new combination treatment of PARPi and RNF6 inhibitor will be tested in PCa cells. Successful completion of the proposed study will provide novel insights into mechanisms underlying PCa progression and therapeutic resistance and lay a foundation for the development of new effective combination treatment of CRPC.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310112
Entities
People
- Yun Qiu
Organizations
- United States Army
- University of Maryland, Baltimore