Mechanisms of the androgen receptor splicing in prostate cancer cells

Oncogene. 2014 Jun 12;33(24):3140-50. doi: 10.1038/onc.2013.284. Epub 2013 Jul 15.


Prostate tumors develop resistance to androgen deprivation therapy (ADT) by multiple mechanisms, one of which is to express constitutively active androgen receptor (AR) splice variants lacking the ligand-binding domain. AR splice variant 7 (AR-V7, also termed AR3) is the most abundantly expressed variant that drives prostate tumor progression under ADT conditions. However, the molecular mechanism by which AR-V7 is generated remains unclear. In this manuscript, we demonstrated that RNA splicing of AR-V7 in response to ADT was closely associated with AR gene transcription initiation and elongation rates. Enhanced AR gene transcription by ADT provides a prerequisite condition that further increases the interactions between AR pre-mRNA and splicing factors. Under ADT conditions, recruitment of several RNA splicing factors to the 3' splicing site for AR-V7 was increased. We identified two RNA splicing enhancers and their binding proteins (U2AF65 and ASF/SF2) that had critical roles in splicing AR pre-mRNA into AR-V7. These data indicate that ADT-induced AR gene transcription rate and splicing factor recruitment to AR pre-mRNA contribute to the enhanced AR-V7 levels in prostate cancer cells.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alternative Splicing / genetics*
  • Androgens / pharmacology
  • Animals
  • Apoptosis
  • Blotting, Northern
  • Blotting, Western
  • Cell Proliferation*
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Immunoprecipitation
  • Male
  • Mice
  • Mice, SCID
  • Prostatic Neoplasms / drug therapy
  • Prostatic Neoplasms / genetics*
  • Prostatic Neoplasms / pathology
  • RNA, Messenger / genetics
  • Real-Time Polymerase Chain Reaction
  • Receptors, Androgen / genetics*
  • Receptors, Androgen / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays


  • AR protein, human
  • Androgens
  • RNA, Messenger
  • Receptors, Androgen