Regulation of u-PAR gene expression by H2A.Z is modulated by the MEK-ERK/AP-1 pathway

Nucleic Acids Res. 2012 Jan;40(2):600-13. doi: 10.1093/nar/gkr725. Epub 2011 Sep 21.


The urokinase receptor (u-PAR) which is largely regulated at the transcriptional level has been implicated in tumor progression. In this study, we explored the epigenetic regulation of u-PAR and showed that the histone variant H2A.Z negatively regulates its expression in multiple cell lines. Chromatin immunoprecipitation assays revealed that H2A.Z was enriched at previously characterized u-PAR-regulatory regions (promoter and a downstream enhancer) and dissociates upon activation of gene expression by phorbol ester (PMA). Using specific chemical and dominant negative expression constructs, we show that the MEK-ERK signaling pathway terminating at AP-1 transcription factors intersects with the epigenetic control of u-PAR expression by H2A.Z. Furthermore, we demonstrate that two other AP-1 targets (MMP9 gene and miR-21 microRNA) are also H2A.Z regulated. In conclusion, our work demonstrates that (i) the expression of two genes and a microRNA all implicated in tumor progression are directly regulated by H2A.Z and (ii) MEK-ERK signaling terminating at AP-1 intersects with the epigenetic control of target gene expression by H2A.Z.

Publication types

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

MeSH terms

  • Binding Sites
  • Cell Line, Tumor
  • Enhancer Elements, Genetic
  • Epigenesis, Genetic*
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Genes, ras
  • Histones / metabolism*
  • Humans
  • MAP Kinase Signaling System*
  • Matrix Metalloproteinase 9 / biosynthesis
  • Matrix Metalloproteinase 9 / genetics
  • MicroRNAs / biosynthesis
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Mutation
  • Promoter Regions, Genetic
  • Receptors, Urokinase Plasminogen Activator / biosynthesis
  • Receptors, Urokinase Plasminogen Activator / genetics*
  • Transcription Factor AP-1 / metabolism*
  • Transcription Factors / metabolism
  • Transcriptional Activation
  • Up-Regulation


  • Histones
  • MicroRNAs
  • Receptors, Urokinase Plasminogen Activator
  • Transcription Factor AP-1
  • Transcription Factors
  • histone H2A.F-Z
  • Extracellular Signal-Regulated MAP Kinases
  • Mitogen-Activated Protein Kinase Kinases
  • Matrix Metalloproteinase 9