Androgen receptor splice variants drive castration-resistant prostate cancer metastasis by activating distinct transcriptional programs

J Clin Invest. 2024 Apr 30;134(11):e168649. doi: 10.1172/JCI168649.

Abstract

One critical mechanism through which prostate cancer (PCa) adapts to treatments targeting androgen receptor (AR) signaling is the emergence of ligand-binding domain-truncated and constitutively active AR splice variants, particularly AR-V7. While AR-V7 has been intensively studied, its ability to activate distinct biological functions compared with the full-length AR (AR-FL), and its role in regulating the metastatic progression of castration-resistant PCa (CRPC), remain unclear. Our study found that, under castrated conditions, AR-V7 strongly induced osteoblastic bone lesions, a response not observed with AR-FL overexpression. Through combined ChIP-seq, ATAC-seq, and RNA-seq analyses, we demonstrated that AR-V7 uniquely accesses the androgen-responsive elements in compact chromatin regions, activating a distinct transcription program. This program was highly enriched for genes involved in epithelial-mesenchymal transition and metastasis. Notably, we discovered that SOX9, a critical metastasis driver gene, was a direct target and downstream effector of AR-V7. Its protein expression was dramatically upregulated in AR-V7-induced bone lesions. Moreover, we found that Ser81 phosphorylation enhanced AR-V7's pro-metastasis function by selectively altering its specific transcription program. Blocking this phosphorylation with CDK9 inhibitors impaired the AR-V7-mediated metastasis program. Overall, our study has provided molecular insights into the role of AR splice variants in driving the metastatic progression of CRPC.

Keywords: Molecular genetics; Oncology; Prostate cancer; Transcription.

MeSH terms

  • Alternative Splicing
  • Animals
  • Bone Neoplasms / genetics
  • Bone Neoplasms / metabolism
  • Bone Neoplasms / pathology
  • Bone Neoplasms / secondary
  • Cell Line, Tumor
  • Epithelial-Mesenchymal Transition / genetics
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Male
  • Mice
  • Neoplasm Metastasis
  • Prostatic Neoplasms, Castration-Resistant* / genetics
  • Prostatic Neoplasms, Castration-Resistant* / metabolism
  • Prostatic Neoplasms, Castration-Resistant* / pathology
  • Protein Isoforms* / genetics
  • Protein Isoforms* / metabolism
  • Receptors, Androgen* / genetics
  • Receptors, Androgen* / metabolism
  • SOX9 Transcription Factor / genetics
  • SOX9 Transcription Factor / metabolism
  • Transcription, Genetic

Substances

  • Receptors, Androgen
  • AR protein, human
  • Protein Isoforms
  • SOX9 Transcription Factor