Cooperativity and equilibrium with FOXA1 define the androgen receptor transcriptional program

Nat Commun. 2014 May 30;5:3972. doi: 10.1038/ncomms4972.

Abstract

The pioneering factor FOXA1 opens chromatin to facilitate androgen receptor (AR) binding to prostate-specific genes. How FOXA1 controls the AR cistrome, however, is incompletely understood. Here we show that AR directly binds chromatin through the androgen response elements (AREs). FOXA1 is not required for AR-chromatin interaction, but instrumental in recruiting AR to low-affinity half-AREs by opening local chromatin around adjacent FKHD sites. Too much FOXA1 creates excessive open chromatin regions, which serve as reservoirs that retain AR via abundant half-AREs, thereby reducing its availability for specific sites. FOXA1 downregulation, by contrast, relinquishes AR to permissively bind AREs across the genome, resulting in substantial AR-binding events and AR target gene expression even in the absence of androgen. Taken together, our data illustrate the mechanistic details by which cooperativity and equilibrium with FOXA1 define AR cistrome and reveal a previously unknown function of FOXA1 in inhibiting AR signalling and castration-resistant prostate cancer growth.

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

  • Cell Line, Tumor
  • Chromatin / metabolism*
  • Gene Expression Regulation, Neoplastic*
  • Hepatocyte Nuclear Factor 3-alpha / metabolism*
  • Humans
  • Male
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms, Castration-Resistant / genetics*
  • Prostatic Neoplasms, Castration-Resistant / metabolism
  • Receptors, Androgen / metabolism*
  • Signal Transduction

Substances

  • AR protein, human
  • Chromatin
  • FOXA1 protein, human
  • Hepatocyte Nuclear Factor 3-alpha
  • Receptors, Androgen

Associated data

  • GEO/GSE55007