Increased nuclear factor I-mediated chromatin access drives transition to androgen receptor splice variant dependence in prostate cancer

• Published in: Cell reports (Cambridge) Vol. 44; no. 1; p. 115089
• Main Authors: Poluben, Larysa, Nouri, Mannan, Liang, Jiaqian, Chen, Shaoyong, Varkaris, Andreas, Ersoy-Fazlioglu, Betul, Voznesensky, Olga, Lee, Irene I., Qiu, Xintao, Cato, Laura, Seo, Ji-Heui, Freedman, Matthew L., Sowalsky, Adam G., Lack, Nathan A., Corey, Eva, Nelson, Peter S., Brown, Myles, Long, Henry W., Russo, Joshua W., Balk, Steven P.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 28.01.2025; Elsevier
• Subjects: Alternative Splicing; androgen receptor; Benzamides; Cell Line, Tumor; chromatin; Chromatin - metabolism; CP: Cancer; CP: Molecular biology; epigenetics; FOXA1; Gene Expression Regulation, Neoplastic; Humans; Male; NFI Transcription Factors - metabolism; Nitriles; nuclear factor I; Phenylthiohydantoin - analogs & derivatives; Phenylthiohydantoin - pharmacology; prostate cancer; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Prostatic Neoplasms, Castration-Resistant - genetics; Prostatic Neoplasms, Castration-Resistant - metabolism; Protein Isoforms - genetics; Protein Isoforms - metabolism; Receptors, Androgen - genetics; Receptors, Androgen - metabolism; transcription; FOXA1; prostate cancer; androgen receptor; transcription; CP: Cancer; CP: Molecular biology; nuclear factor I; chromatin; epigenetics
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2024.115089

Androgen receptor (AR) splice variants, of which ARv7 is the most common, are increased in castration-resistant prostate cancer, but the extent to which they drive AR activity is unclear. We generated a subline of VCaP cells (VCaP16) that is resistant to the AR inhibitor enzalutamide (ENZ). AR activity in VCaP16 is driven by ARv7, independently of full-length AR (ARfl), and its cistrome and transcriptome mirror those of ARfl in VCaP cells. ARv7 expression increases rapidly in response to ENZ, but there is a delay in gaining chromatin binding and transcriptional activity, which is associated with increased chromatin accessibility. AR and nuclear factor I (NFI) motifs are most enriched at more accessible sites, and NFIB/X knockdown greatly diminishes ARv7 function. These findings indicate that ARv7 can drive the AR program but that its activity is dependent on adaptations that increase chromatin accessibility to enhance its intrinsically weak chromatin binding. [Display omitted] •AR activity in PC cells treated with AR antagonist (ENZ) is driven by AR splice variant ARv7•ARv7 activity in ENZ-resistant cells is independent of the full-length AR•ARv7 function requires adaptations associated with increased chromatin accessibility•NFI transcription factors are associated with chromatin opening and support ARv7 function Poluben et al. show that prostate cancer cell resistance to an androgen receptor (AR) antagonist targeting the full-length AR (ARfl) is driven by an AR spice variant (ARv7) that functions independently of ARfl but requires adaptations associated with increased chromatin accessibility and is dependent on nuclear factor I transcription factors.