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

Cell Rep. 2025 Jan 28;44(1):115089. doi: 10.1016/j.celrep.2024.115089. Epub 2024 Dec 21.

Abstract

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.

Keywords: CP: Cancer; CP: Molecular biology; FOXA1; androgen receptor; chromatin; epigenetics; nuclear factor I; prostate cancer; transcription.

MeSH terms

  • Alternative Splicing / genetics
  • Benzamides / pharmacology
  • Cell Line, Tumor
  • Chromatin* / metabolism
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Male
  • NFI Transcription Factors* / genetics
  • NFI Transcription Factors* / metabolism
  • Nitriles / pharmacology
  • Phenylthiohydantoin* / pharmacology
  • Prostatic Neoplasms* / genetics
  • Prostatic Neoplasms* / metabolism
  • Prostatic Neoplasms* / pathology
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Receptors, Androgen* / genetics
  • Receptors, Androgen* / metabolism

Substances

  • Receptors, Androgen
  • Chromatin
  • NFI Transcription Factors
  • enzalutamide
  • Phenylthiohydantoin
  • Benzamides
  • Nitriles
  • Protein Isoforms
  • AR protein, human