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

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

ONCOGENE

NATURE PUBLISHING GROUP

Año: 2020

0950-9232

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.