AR-V7 exhibits non-canonical mechanisms of nuclear import and chromatin engagement in castrate-resistant prostate cancer
Abstract
Expression of the AR splice variant, androgen receptor variant 7 (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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jul 18, 2022
- Source ID
- 10.7554/elife.73396
Entities
People
- Adeline Berger
- CheukMan C. Au
- Daniel Worroll
- David M. Nanus
- David S. Rickman
- Eiman Mukhtar
- Luigi Portella
- Mohd Azrin Bin Jamalruddin
- Naira Essam Abou-Ghali
- Paraskevi Giannakakou
- Prerna Vatsa
- Seaho Kim
Organizations
- National Cancer Institute
- United States Department of Defense
- Weill Cornell Medicine