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-a/b 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.
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All data generated or analysed during this study are included in the manuscript. Source data files have been provided for figure 6.
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Funding
National Cancer Institute (NIH T32 CA203702)
- Seaho Kim
National Cancer Institute (NIH T32 CA062948)
- CheukMan C Au
National Cancer Institute (R01CA137020)
- Paraskevi Giannakakou
National Cancer Institute (R21CA216800)
- Paraskevi Giannakakou
National Cancer Institute (R01CA228512)
- Paraskevi Giannakakou
National Cancer Institute (R01CA179100)
- David S Rickman
- Paraskevi Giannakakou
U.S. Department of Defense (W81XWH-17-1-0162)
- Adeline Berger
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2022, Kim et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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