Selective degradation of AR-V7 to overcome castration resistance of prostate cancer.
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.
Mesh Terms:
Animals, Benzamides, Cell Cycle Checkpoints, Cell Line, Tumor, Cell Proliferation, Flavones, Humans, Lysine, Male, Mice, Inbred BALB C, Mice, Nude, Models, Biological, Nitriles, Phenylthiohydantoin, Prostatic Neoplasms, Castration-Resistant, Proteasome Endopeptidase Complex, Proteolysis, Receptors, Androgen, Ubiquitin Thiolesterase, Ubiquitination
Animals, Benzamides, Cell Cycle Checkpoints, Cell Line, Tumor, Cell Proliferation, Flavones, Humans, Lysine, Male, Mice, Inbred BALB C, Mice, Nude, Models, Biological, Nitriles, Phenylthiohydantoin, Prostatic Neoplasms, Castration-Resistant, Proteasome Endopeptidase Complex, Proteolysis, Receptors, Androgen, Ubiquitin Thiolesterase, Ubiquitination
Cell Death Dis
Date: Dec. 21, 2020
PubMed ID: 34548474
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