Abstract
Metastatic castration-resistant prostate cancer (mCRPC) is an aggressive and fatal disease, with most patients succumbing within 1-2 years despite undergoing multiple treatments. Androgen-receptor (AR) inhibitors, including enzalutamide (ENZ), are used for the treatment of mCRPC; however, most patients develop resistance to ENZ. Herein, we propose that the repression of SLC22A3 by AR-V7/YAP1/TAZ conferred ENZ resistance in mCRPC. SLC22A3 expression is specifically downregulated in the ENZ-resistant C4-2B MDVR cells, and when YAP1/TAZ is hyperactivated by AR full-length or AR-V7, these proteins interact with DNMT1 to repress SLC22A3 expression. We observed low SLC22A3 expression and high levels of TAZ or YAP1 in mCRPC patient tissues harbouring AR-V7 and the opposite expression patterns in normal patient tissues. Our findings suggest a mechanism underlying ENZ resistance by providing evidence that the AR-V7/YAP1/TAZ axis represses SLC22A3, which could be a potential treatment target in prostate cancer.
Keywords:
AR-V7; SLC22A3; TAZ; YAP1; enzalutamide resistance.
© 2022 Federation of European Biochemical Societies.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Androgen Receptor Antagonists* / pharmacology
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Androgen Receptor Antagonists* / therapeutic use
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Antineoplastic Agents, Hormonal* / pharmacology
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Antineoplastic Agents, Hormonal* / therapeutic use
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Drug Resistance, Neoplasm* / genetics
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Humans
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Male
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Nitriles / pharmacology
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Nitriles / therapeutic use
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Organic Cation Transport Proteins* / metabolism
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Phenylthiohydantoin / pharmacology
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Phenylthiohydantoin / therapeutic use
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Prostatic Neoplasms, Castration-Resistant* / drug therapy
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Prostatic Neoplasms, Castration-Resistant* / genetics
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Prostatic Neoplasms, Castration-Resistant* / metabolism
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Prostatic Neoplasms, Castration-Resistant* / secondary
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Receptors, Androgen / genetics
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Receptors, Androgen / metabolism
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Transcriptional Coactivator with PDZ-Binding Motif Proteins / metabolism
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YAP-Signaling Proteins* / metabolism
Substances
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Androgen Receptor Antagonists
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Antineoplastic Agents, Hormonal
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enzalutamide
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Nitriles
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Organic Cation Transport Proteins
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Phenylthiohydantoin
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Receptors, Androgen
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solute carrier family 22 (organic cation transporter), member 3
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Transcriptional Coactivator with PDZ-Binding Motif Proteins
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WWTR1 protein, human
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YAP-Signaling Proteins