Androgen Receptor Splice Variants Dimerize to Transactivate Target Genes

Cancer Res. 2015 Sep 1;75(17):3663-71. doi: 10.1158/0008-5472.CAN-15-0381. Epub 2015 Jun 9.


Constitutively active androgen receptor splice variants (AR-V) lacking the ligand-binding domain have been implicated in the pathogenesis of castration-resistant prostate cancer and in mediating resistance to newer drugs that target the androgen axis. AR-V regulates expression of both canonical AR targets and a unique set of cancer-specific targets that are enriched for cell-cycle functions. However, little is known about how AR-V controls gene expression. Here, we report that two major AR-Vs, termed AR-V7 and AR(v567es), not only homodimerize and heterodimerize with each other but also heterodimerize with full-length androgen receptor (AR-FL) in an androgen-independent manner. We found that heterodimerization of AR-V and AR-FL was mediated by N- and C-terminal interactions and by the DNA-binding domain of each molecule, whereas AR-V homodimerization was mediated only by DNA-binding domain interactions. Notably, AR-V dimerization was required to transactivate target genes and to confer castration-resistant cell growth. Our results clarify the mechanism by which AR-Vs mediate gene regulation and provide a pivotal pathway for rational drug design to disrupt AR-V signaling as a rational strategy for the effective treatment of advanced prostate cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing / genetics
  • Androgens / genetics
  • Cell Line, Tumor
  • DNA-Binding Proteins
  • Humans
  • Ligands
  • Male
  • Prostatic Neoplasms, Castration-Resistant / genetics*
  • Prostatic Neoplasms, Castration-Resistant / pathology
  • Protein Isoforms / genetics*
  • Protein Multimerization
  • Protein Structure, Tertiary
  • Receptors, Androgen / genetics*
  • Receptors, Androgen / metabolism


  • AR protein, human
  • Androgens
  • DNA-Binding Proteins
  • Ligands
  • Protein Isoforms
  • Receptors, Androgen