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A detailed characterization of stepwise activation of the androgen receptor variant 7 in prostate cancer cells

Oncogene volume 40, pages 1106–1117 (2021)Cite this article

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Abstract

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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Fig. 1: AR-V7/-FL or AR-V7/-V7 dimerization does not require other factors or DNA-binding.
Fig. 2: AR-V7 does not significantly affect AR-FL ligand binding.
Fig. 3: FXXLF motif is critical for AR-V7/-FL heterodimerization.
Fig. 4: Dimerization with AR-FL is required for AR-V7 to induce nuclear localization of unliganded AR-FL.
Fig. 5: Subcellular localization of AR-V7 mutants.
Fig. 6: AR-V7 retains the ability to drive transcription independently of heterodimerization with AR-FL.
Fig. 7: Homodimerization and DNA binding, but not dimerization with AR-FL, is required for AR-V7 to mediate DNA-damage repair.

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Acknowledgements

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.

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Author notes

  1. These authors contributed equally: Carlos M. Roggero, Lianjin Jin, Subing Cao

Authors and Affiliations

  1. Department of Urology, UT Southwestern Medical Center at Dallas, Dallas, TX, USA

    Carlos M. Roggero, Rajni Sonavane, Noa G. Kopplin, Dede N. Ekoue, Michael Witwer, Shihong Ma & Ganesh V. Raj

  2. Department of Structural and Cellular Biology, Tulane University School of Medicine, Tulane Cancer Center, New Orleans, LA, USA

    Lianjin Jin, Subing Cao, Tianfang Ma & Yan Dong

  3. Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA, USA

    Huy Q. Ta & Daniel Gioeli

  4. Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, LA, USA

    Hong Liu

  5. Department of Pharmacology, UT Southwestern Medical Center at Dallas, Dallas, TX, USA

    Ganesh V. Raj

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Correspondence to Ganesh V. Raj or Yan Dong.

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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.

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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

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