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    The PAX8 cistrome in epithelial ovarian cancer.

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    Authors
    Adler, Emily K.
    Corona, Rosario I.
    Lee, Janet M.
    Rodriguez-Malave, Norma
    Mhawech-Fauceglia, Paulette
    Sowter, Heidi M. cc
    Hazelett, Dennis J.
    Lawrenson, Kate
    Gayther, Simon A.
    Affiliation
    University of Southern California
    Cedars-Sinai Medical Center
    University of Derby
    Issue Date
    2017-11-28
    
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    Abstract
    PAX8 is a lineage-restricted transcription factor that is expressed in epithelial ovarian cancer (EOC) precursor tissues, and in the major EOC histotypes. Frequent overexpression of PAX8 in primary EOCs suggests this factor functions as an oncogene during tumorigenesis, however, the biological role of PAX8 in EOC development is poorly understood. We found that stable knockdown of PAX8 in EOC models significantly reduced cell proliferation and anchorage dependent growth in vitro, and attenuated tumorigenicity in vivo. Chromatin immunoprecipitation followed by next generation sequencing (ChIP-seq) and transcriptional profiling were used to create genome-wide maps of PAX8 binding and putative target genes. PAX8 binding sites were significantly enriched in promoter regions (p < 0.05) and superenhancers (p < 0.05). MEME-ChIP analysis revealed that PAX8 binding sites overlapping superenhancers or enhancers, but not promoters, were enriched for JUND/B and ARNT/AHR motifs. Integrating PAX8 ChIP-seq and gene expression data identified PAX8 target genes through their associations within shared topological association domains. Across two EOC models we identified 62 direct regulatory targets based on PAX8 binding in promoters and 1,330 putative enhancer regulatory targets. SEPW1, which isinvolved inoxidation-reduction,was identified as a PAX8 target gene in both cell line models. While the PAX8 cistrome exhibits a high degree of cell-type specificity, analyses of PAX8 target genes and putative cofactors identified common molecular targets and partners as candidate therapeutic targets for EOC.
    Citation
    Adler, E. K. et al (2017) 'The PAX8 cistrome in epithelial ovarian cancer', Oncotarget, 8 (65).
    Publisher
    Impact Journals
    Journal
    Oncotarget
    URI
    http://hdl.handle.net/10545/622076
    DOI
    10.18632/oncotarget.22718
    Additional Links
    http://www.oncotarget.com/fulltext/22718
    Type
    Article
    Language
    en
    ISSN
    19492553
    ae974a485f413a2113503eed53cd6c53
    10.18632/oncotarget.22718
    Scopus Count
    Collections
    School of Environmental Sciences

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