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Updated: Oct 19, 2025
Sequencing Small Non-coding RNA from Formalin-fixed Tissues and Serum-derived Exosomes from Castration-resistant Prostate Cancer Patients
Published on: November 19, 2019
Selective degradation of AR-V7 to overcome castration resistance of prostate cancer
Yuan Liu1,2, Cuifu Yu1,2, Zhenlong Shao2
1Affiliated Cancer Hospital & Institute of Guangzhou Medical University, 510095, Guangzhou, Guangdong, China.
Abstract:
Androgen receptor splice variant 7 (AR-V7), a form of ligand-independent and constitutively activating variant of androgen receptor (AR), is considered as the key driver to initiate castration-resistant prostate cancer (CRPC). Because AR-V7 lacks ligand-binding domain, the AR-targeted therapies that aim to inactivate AR signaling through disrupting the interaction between AR and androgen are limited in CRPC. Thus, the emergence of AR-V7 has become the greatest challenge for treating CRPC. Targeting protein degradation is a recently proposed novel avenue for cancer treatment. Our previous studies have been shown that the oncoprotein AR-V7 is a substrate of the proteasome. Identifying novel drugs that can trigger the degradation of AR-V7 is therefore critical to cure CRPC. Here we show that nobiletin, a polymethoxylated flavonoid derived from the peel of Citrus fruits, exerts a potent anticancer activity via inducing G0/G1 phase arrest and enhancing the sensitivity of cells to enzalutamide in AR-V7 positive PC cells. Mechanically, we unravel that nobiletin selectively induces proteasomal degradation of AR-V7 (but not AR). This effect relies on its selective inhibition of the interactions between AR-V7 and two deubiquitinases USP14 and USP22. These findings not only enrich our understanding on the mechanism of AR-V7 degradation, but also provide an efficient and druggable target for overcoming CRPC through interfering the stability of AR-V7 mediated by the interaction between AR-V7 and deubiquitinase.
Insights
Nobiletin, a citrus flavonoid, combats castration-resistant prostate cancer (CRPC) by selectively degrading the AR-V7 oncoprotein. This novel approach targets AR-V7 protein degradation, offering a new strategy against CRPC.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Androgen receptor splice variant 7 (AR-V7) drives castration-resistant prostate cancer (CRPC) by constitutively activating androgen receptor (AR) signaling.
- The lack of a ligand-binding domain in AR-V7 limits the efficacy of current AR-targeted therapies in CRPC.
- Targeting protein degradation pathways presents a novel therapeutic strategy for cancers, including CRPC.
Purpose of the Study:
- To identify novel drugs that induce proteasomal degradation of the AR-V7 oncoprotein.
- To investigate the anticancer activity and mechanism of nobiletin in AR-V7 positive prostate cancer cells.
Main Methods:
- Assessed the effect of nobiletin on cell cycle progression (G0/G1 arrest) and enzalutamide sensitivity in AR-V7 positive prostate cancer cells.
- Investigated the impact of nobiletin on AR-V7 and AR protein levels using proteasomal degradation assays.
- Elucidated the mechanism by examining nobiletin's effect on the interaction between AR-V7 and deubiquitinases USP14 and USP22.
Main Results:
- Nobiletin demonstrated potent anticancer activity by inducing G0/G1 phase arrest and enhancing enzalutamide sensitivity in AR-V7 positive prostate cancer cells.
- Nobiletin selectively induced proteasomal degradation of AR-V7, but not wild-type AR.
- Nobiletin's mechanism involves the selective inhibition of interactions between AR-V7 and deubiquitinases USP14 and USP22.
Conclusions:
- Nobiletin is a promising therapeutic agent for CRPC, acting through the selective degradation of AR-V7.
- Interfering with the stability of AR-V7 via its interaction with deubiquitinases represents a druggable target for overcoming CRPC.
- These findings provide new insights into AR-V7 degradation mechanisms and offer a novel strategy for CRPC treatment.
