AR-V7 exhibits non-canonical mechanisms of nuclear import and chromatin engagement in Castrate-Resistant Prostate Cancer

Abstract

Expression of the AR splice variant, AR-V7, in prostate cancer is correlated with poor patient survival and resistance to AR targeted therapies and taxanes. Currently, there is no specific inhibitor of AR-V7, while the molecular mechanisms regulating its biological function are not well elucidated. Here we report that AR-V7 has unique biological features that functionally differentiate it from canonical AR-fl or from the second most prevalent variant, AR-v567. First, AR-V7 exhibits fast nuclear import kinetics via a pathway distinct from the nuclear localization signal dependent importin-α/β pathway used by AR-fl and AR-v567. We also show that the dimerization box domain, known to mediate AR dimerization and transactivation, is required for AR-V7 nuclear import but not for AR-fl. Once in the nucleus, AR-V7 is transcriptionally active, yet exhibits unusually high intranuclear mobility and transient chromatin interactions, unlike the stable chromatin association of liganded AR-fl. The high intranuclear mobility of AR-V7 together with its high transcriptional output, suggest a Hit-and-Run mode of transcription. Our findings reveal unique mechanisms regulating AR-V7 activity, offering the opportunity to develop selective therapeutic interventions.

A novel inhibitor of ARfl and ARv7 induces protein degradation to overcome enzalutamide resistance in advanced prostate cancer

“…These results suggest that LLU-206 may function as a molecular glue, which can degrade proteins (including ARv7) by orchestrating direct interactions between target and ligase 44 , 45 . In addition, ARv7 functioning requires heterodimerization with ARfl by the interaction of the ARfl C-terminal with the N-terminal FxxLF motif in ARv7 and by the DNA-binding domain of ARfl or ARv7 21 , 46 , 47 . Dimerization is an absolute and indispensable requirement for constitutive ARv7 DNA-binding and transcriptional activation function.…”

Sex Differences in Taxane Toxicities

“…The capability of tumors to preferentially shuttle AR through nuclear transport is thought to contribute to taxane resistance in prostate cancer. The ability to circumvent microtubule transport machinery has been demonstrated by AR-V7, which is a commonly found AR splice variant that lacks the hinging domain necessary to attach to the tubulin-dynein transporter molecule for minus-end (nuclear) microtubule transport [ 149 ]. The identification of AR-V7 splice variants in tumors is associated with advanced CRPC, taxane resistance, and reduced patient survival [ 150 , 151 , 152 , 153 , 154 , 155 ].…”