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

• Published in: Oncogene Vol. 40; no. 6; pp. 1106 - 1117
• Main Authors: Roggero, Carlos M., Jin, Lianjin, Cao, Subing, Sonavane, Rajni, Kopplin, Noa G., Ta, Huy Q., Ekoue, Dede N., Witwer, Michael, Ma, Shihong, Liu, Hong, Ma, Tianfang, Gioeli, Daniel, Raj, Ganesh V., Dong, Yan
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 11.02.2021; Nature Publishing Group
• Subjects: 13/106; 13/109; 14/19; 14/63; 38/91; 631/67/395; 631/67/589/466; 82/80; Alternative splicing; Androgen receptors; Androgens; Apoptosis; Care and treatment; Cell Biology; Cofactors; Deoxyribonucleic acid; Development and progression; DNA; DNA damage; DNA repair; Gene expression; Genetic aspects; Genetic variation; Health aspects; Human Genetics; Internal Medicine; Localization; Medicine; Medicine & Public Health; Oncology; Prostate cancer; Transcription; United States
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-020-01585-5

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.