Androgen regulation of the TMPRSS2 gene and the effect of a SNP in an androgen response element

Mol Endocrinol. 2013 Dec;27(12):2028-40. doi: 10.1210/me.2013-1098. Epub 2013 Oct 9.

Abstract

More than 50% of prostate cancers have undergone a genomic reorganization that juxtaposes the androgen-regulated promoter of TMPRSS2 and the protein coding parts of several ETS oncogenes. These gene fusions lead to prostate-specific and androgen-induced ETS expression and are associated with aggressive lesions, poor prognosis, and early-onset prostate cancer. In this study, we showed that an enhancer at 13 kb upstream of the TMPRSS2 transcription start site is crucial for the androgen regulation of the TMPRSS2 gene when tested in bacterial artificial chromosomal vectors. Within this enhancer, we identified the exact androgen receptor binding sequence. This newly identified androgen response element is situated next to two binding sites for the pioneer factor GATA2, which were identified by DNase I footprinting. Both the androgen response element and the GATA-2 binding sites are involved in the enhancer activity. Importantly, a single nucleotide polymorphism (rs8134378) within this androgen response element reduces binding and transactivation by the androgen receptor. The presence of this SNP might have implications on the expression and/or formation levels of TMPRSS2 fusions, because both have been shown to be influenced by androgens.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androgens / pharmacology*
  • Animals
  • Base Pairing / genetics
  • Base Sequence
  • Binding Sites / genetics
  • COS Cells
  • Cell Line, Tumor
  • Chlorocebus aethiops
  • Chromatin / metabolism
  • Enhancer Elements, Genetic
  • GATA2 Transcription Factor / metabolism
  • Gene Expression Regulation / drug effects
  • Humans
  • Molecular Sequence Data
  • Organic Cation Transporter 1 / metabolism
  • Polymorphism, Single Nucleotide / genetics*
  • Protein Binding / drug effects
  • Protein Binding / genetics
  • Response Elements / genetics*
  • Serine Endopeptidases / genetics*

Substances

  • Androgens
  • Chromatin
  • GATA2 Transcription Factor
  • Organic Cation Transporter 1
  • Serine Endopeptidases
  • TMPRSS2 protein, human

Grant support

This study was financially supported by the Agency for Innovation by Science and Technology in Flanders (IWT), by Grant OT/09/035 from the Katholieke Universiteit Leuven, and Grant numbers G.0684.12 and G.0830.13 of the Fund for Scientific Research Flanders, Belgium (FWO-Vlaanderen). V.D. and M.L. are holders of an FWO doctoral fellowship. S.J. is holder of a grant from the Klinisch Onderzoeksfonds (KOF) from UZ Leuven.