ZFX Mediates Non-canonical Oncogenic Functions of the Androgen Receptor Splice Variant 7 in Castrate-Resistant Prostate Cancer

Mol Cell. 2018 Oct 18;72(2):341-354.e6. doi: 10.1016/j.molcel.2018.08.029. Epub 2018 Sep 27.

Abstract

Androgen receptor splice variant 7 (AR-V7) is crucial for prostate cancer progression and therapeutic resistance. We show that, independent of ligand, AR-V7 binds both androgen-responsive elements (AREs) and non-canonical sites distinct from full-length AR (AR-FL) targets. Consequently, AR-V7 not only recapitulates AR-FL's partial functions but also regulates an additional gene expression program uniquely via binding to gene promoters rather than ARE enhancers. AR-V7 binding and AR-V7-mediated activation at these unique targets do not require FOXA1 but rely on ZFX and BRD4. Knockdown of ZFX or select unique targets of AR-V7/ZFX, or BRD4 inhibition, suppresses growth of castration-resistant prostate cancer cells. We also define an AR-V7 direct target gene signature that correlates with AR-V7 expression in primary tumors, differentiates metastatic prostate cancer from normal, and predicts poor prognosis. Thus, AR-V7 has both ARE/FOXA1 canonical and ZFX-directed non-canonical regulatory functions in the evolution of anti-androgen therapeutic resistance, providing information to guide effective therapeutic strategies.

Keywords: AR-V7; BRD4; Enzalutamide; MDV3100; ZFX; androgen receptor; bromodomain inhibitor; castration resistance; prostate cancer; therapy resistance.

Publication types

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

MeSH terms

  • Alternative Splicing / genetics*
  • Animals
  • Carcinogenesis / genetics*
  • Cell Differentiation / genetics
  • Cell Line
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm / genetics
  • Gene Expression Regulation, Neoplastic / genetics
  • HEK293 Cells
  • Hepatocyte Nuclear Factor 3-alpha / genetics
  • Humans
  • Kruppel-Like Transcription Factors / genetics*
  • Male
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Nuclear Proteins / genetics
  • Oncogenes / genetics*
  • Promoter Regions, Genetic / genetics
  • Prostatic Neoplasms, Castration-Resistant / genetics*
  • Receptors, Androgen / genetics*

Substances

  • Hepatocyte Nuclear Factor 3-alpha
  • Kruppel-Like Transcription Factors
  • Nuclear Proteins
  • Receptors, Androgen
  • zinc finger protein, X-linked