Expression of the androgen receptor splice variant 7 (AR-V7) is frequently detected in castrate resistant prostate cancer and associated with resistance to AR-targeted therapies. While we have previously noted that homodimerization is required for the transcriptional activity of AR-V7 and that AR-V7 can also form heterodimers with the full-length AR (AR-FL), there are still many gaps of knowledge in AR-V7 stepwise activation. In the present study, we show that neither AR-V7 homodimerization nor AR-V7/AR-FL heterodimerization requires cofactors or DNA binding. AR-V7 can enter the nucleus as a monomer and drive a transcriptional program and DNA-damage repair as a homodimer. While forming a heterodimer with AR-FL to induce nuclear localization of unliganded AR-FL, AR-V7 does not need to interact with AR-FL to drive gene transcription or DNA-damage repair in prostate cancer cells that co-express AR-V7 and AR-FL. These data indicate that AR-V7 can function independently of its interaction with AR-FL in the true castrate state or “absence of ligand”, providing support for the utility of targeting AR-V7 in improving outcomes of patients with castrate resistant prostate cancer.
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We are grateful to Dr. Stephen Plymate at the University of Washington for providing cumate-inducible AR-V7 expression construct. We appreciate the support from the Tulane Cancer Next Generation Sequence Analysis core for utilization of resources and expertise for this work.
Conflict of interest
This work was funded by grants from the Department of Defense (W81XWH-19-1-0363, W81XWH-17-1-0674), Prostate Cancer Foundation Challenge Award, Mimi and John Cole Foundation and Charles Y. Pak grant to GVR, from the National Institutes of Health (R01CA188609) and the Department of Defense (W81XWH-15-1-0439 and W81XWH-16-1-0317) to YD, and from the National Institutes of Health (R01 CA178338) to DG. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Dedication: This paper is dedicated to the memory of Amy Rui Li, lab manager of the Raj laboratory, who lost her battle with cancer.
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Roggero, C.M., Jin, L., Cao, S. et al. A detailed characterization of stepwise activation of the androgen receptor variant 7 in prostate cancer cells. Oncogene 40, 1106–1117 (2021). https://doi.org/10.1038/s41388-020-01585-5