title: Regulation of u-PAR gene expression by H2A.Z is modulated by the MEK-ERK/AP-1 pathway.
abstract: 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.
authors.affiliation: Department of Cancer Biology, MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Santosh
authors.initials: S
authors.lastname: Chauhan
authors.forename: Douglas D
authors.initials: DD
authors.lastname: Boyd
mesh_terms: D001665:Binding Sites; D045744:Cell Line, Tumor; D004742:Enhancer Elements, Genetic; D044127:Epigenesis, Genetic; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D011905:Genes, ras; D006657:Histones / Q000378:metabolism*; D006801:Humans; D020935:MAP Kinase Signaling System; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000235:genetics; D035683:MicroRNAs / Q000096:biosynthesis; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009154:Mutation; D011401:Promoter Regions, Genetic; D055293:Receptors, Urokinase Plasminogen Activator / Q000096:biosynthesis / Q000235:genetics*; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation; D015854:Up-Regulation
chemical_list: D006657:Histones; D035683:MicroRNAs; D055293:Receptors, Urokinase Plasminogen Activator; D018808:Transcription Factor AP-1; D014157:Transcription Factors; C077020:histone H2A.F-Z; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D020780:Matrix Metalloproteinase 9