Definition of a FoxA1 Cistrome that is crucial for G1 to S-phase cell-cycle transit in castration-resistant prostate cancer

Cancer Res. 2011 Nov 1;71(21):6738-6748. doi: 10.1158/0008-5472.CAN-11-1882. Epub 2011 Sep 7.


The enhancer pioneer transcription factor FoxA1 is a global mediator of steroid receptor (SR) action in hormone-dependent cancers. In castration-resistant prostate cancer (CRPC), FoxA1 acts as an androgen receptor cofactor to drive G₂ to M-phase cell-cycle transit. Here, we describe a mechanistically distinct SR-independent role for FoxA1 in driving G₁ to S-phase cell-cycle transit in CRPC. By comparing FoxA1 binding sites in prostate cancer cell genomes, we defined a codependent set of FoxA1-MYBL2 and FoxA1-CREB1 binding sites within the regulatory regions of the Cyclin E2 and E2F1 genes that are critical for CRPC growth. Binding at these sites upregulate the Cyclin E2 and Cyclin A2 genes in CRPC but not in earlier stage androgen-dependent prostate cancer, establishing a stage-specific role for this pathway in CRPC growth. Mechanistic investigations indicated that FoxA1, MYBL2, or CREB1 induction of histone H3 acetylation facilitated nucleosome disruption as the basis for codependent transcriptional activation and G₁ to S-phase cell-cycle transit. Our findings establish FoxA1 as a pivotal driver of the cell-cycle in CRPC which promotes G₁ to S-phase transit as well as G₂ to M-phase transit through two distinct mechanisms.

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

  • Adenocarcinoma / genetics*
  • Adenocarcinoma / pathology
  • Androgens
  • Binding Sites
  • Cell Cycle Proteins / metabolism
  • Cell Line, Tumor
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Cyclin A2 / biosynthesis
  • Cyclin A2 / genetics
  • Disease Progression
  • E2F1 Transcription Factor / biosynthesis
  • E2F1 Transcription Factor / genetics
  • G1 Phase / physiology*
  • G2 Phase / physiology
  • Hepatocyte Nuclear Factor 3-alpha / physiology*
  • Humans
  • In Vitro Techniques
  • Male
  • Metaphase / physiology
  • Neoplasm Proteins / physiology*
  • Neoplasms, Hormone-Dependent / genetics
  • Neoplasms, Hormone-Dependent / pathology
  • Nucleosomes / metabolism
  • Prostatic Neoplasms / genetics*
  • Prostatic Neoplasms / pathology
  • Regulatory Sequences, Nucleic Acid
  • S Phase / physiology*
  • Trans-Activators / metabolism


  • Androgens
  • CCNA2 protein, human
  • CREB1 protein, human
  • Cell Cycle Proteins
  • Cyclic AMP Response Element-Binding Protein
  • Cyclin A2
  • E2F1 Transcription Factor
  • E2F1 protein, human
  • FOXA1 protein, human
  • Hepatocyte Nuclear Factor 3-alpha
  • MYBL2 protein, human
  • Neoplasm Proteins
  • Nucleosomes
  • Trans-Activators