Androgen receptor splice variant 7 functions independently of the full length receptor in prostate cancer cells. (28th October 2021)

• Record Type: Journal Article
• Authors: Liang, Jiaqian; Wang, Liyang; Poluben, Larysa; Nouri, Mannan; Arai, Seiji; Xie, Lisha; Voznesensky, Olga S.; Cato, Laura; Yuan, Xin; Russo, Joshua W.; Long, Henry W.; Brown, Myles; Chen, Shaoyong; Balk, Steven P.
• Is Part Of: Cancer letters. Volume 519(2021)
• Page Start: 172
• Page End: 184
• Publication Date: 2021-10-28
• Subjects: Androgen receptor -- Androgen receptor splice variants -- Prostate cancer -- Castration-resistant prostate cancer -- Chromatin; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2021.07.013
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: One mechanism for reactivation of androgen receptor (AR) activity after androgen deprivation therapy in castration-resistant prostate cancer (CRPC) is expression of splice variants such as ARv7 that delete the ligand binding domain and have constitutive activity. Exogenous overexpressed ARv7 can function as a homodimer or heterodimer with full length AR (ARfl), which is highly expressed with ARv7 in CRPC. However, the extent to which endogenous ARv7 function is dependent on heterodimerization with ARfl remains to be determined. We used double-crosslinking to stabilize AR complexes on chromatin in a CRPC cell line expressing endogenous ARfl and ARv7 (LN95 cells), and established that only trace levels of ARfl were associated with ARv7 on chromatin. Consistent with this result, depletion of ARfl with an AR degrader targeting the AR ligand binding domain did not decrease ARv7 binding to chromatin or its association with HOXB13, but did decrease overall AR transcriptional activity. Comparable results were obtained in CWR22RV1 cells, another CRPC cell line expressing ARfl and ARv7. These results indicate that ARv7 function in CRPC is not dependent on ARfl, and that both contribute independently to overall AR activity. Highlights: AR full length depletion does not impair ARv7 splice variant chromatin binding. AR full length depletion variably decreases overall AR transcriptional activity. AR full length and ARv7 contribute independently to AR transcriptional activity.