Functional genomic analysis reveals cross-talk between peroxisome proliferator-activated receptor γ and calcium signaling in human colorectal cancer cells

Craig R. Bush, Jennifer M. Havens, Brian M. Necela, Weidong Su, Lu Chen, Masahiro Yanagisawa, Panos Z. Anastasiadis, Rudy Guerra, Bruce A. Luxon, E. Aubrey Thompson

    Research output: Contribution to journalArticle

    22 Citations (Scopus)

    Abstract

    Activation of PPARγ in MOSER cells inhibits anchorage-dependent and anchorage-independent growth and invasion through Matrigel-coated transwell membranes. We carried out a longitudinal two-class microarray analysis in which mRNA abundance was measured as a function of time in cells treated with a thiazolidinedione PPARγ agonist or vehicle. A statistical machine learning algorithm that employs an empirical Bayesian implementation of the multivariate HotellingT2 score was used to identify differentially regulated genes. HotellingT2 scores, MB statistics, and maximum median differences were used as figures of merit to interrogate genomic ontology of these targets. Three major cohorts of genes were regulated: those involved in metabolism, DNA replication, and migration/motility, reflecting the cellular phenotype that attends activation of PPARγ. The bioinformatic analysis also inferred that PPARγ regulates calcium signaling. This response was unanticipated, because calcium signaling has not previously been associated with PPARγ activation. Ingenuity pathway analysis inferred that the nodal point in this cross-talk was Down syndrome critical region 1 (DSCR1). DSCR1 is an endogenous calcineurin inhibitor that blocks dephosphorylation and activation of members of the cytoplasmic component of nuclear factor of activated T cells transcription factors. Lentiviral short hairpin RNA-mediated knockdown of DSCR1 blocks PPARγ inhibition of proliferation and invasion, indicating that DSCR1 is required for suppression of transformed properties of early stage colorectal cancer cells by PPARγ. These data reveal a novel, heretofore unappreciated link between PPARγ and calcium signaling and indicate that DSCR1, which has previously been thought to function by suppression of the angiogenic response in endothelial cells, may also play a direct role in transformation of epithelial cells.

    Original languageEnglish (US)
    Pages (from-to)23387-23401
    Number of pages15
    JournalJournal of Biological Chemistry
    Volume282
    Issue number32
    DOIs
    StatePublished - Aug 10 2007

    Fingerprint

    Peroxisome Proliferator-Activated Receptors
    Calcium Signaling
    Colorectal Neoplasms
    Cells
    Calcium
    Chemical activation
    Genes
    NFATC Transcription Factors
    TCF Transcription Factors
    Endothelial cells
    Microarray Analysis
    Bioinformatics
    Microarrays
    Computational Biology
    DNA Replication
    Metabolism
    Learning algorithms
    Small Interfering RNA
    Ontology
    Learning systems

    ASJC Scopus subject areas

    • Biochemistry

    Cite this

    Functional genomic analysis reveals cross-talk between peroxisome proliferator-activated receptor γ and calcium signaling in human colorectal cancer cells. / Bush, Craig R.; Havens, Jennifer M.; Necela, Brian M.; Su, Weidong; Chen, Lu; Yanagisawa, Masahiro; Anastasiadis, Panos Z.; Guerra, Rudy; Luxon, Bruce A.; Thompson, E. Aubrey.

    In: Journal of Biological Chemistry, Vol. 282, No. 32, 10.08.2007, p. 23387-23401.

    Research output: Contribution to journalArticle

    Bush, CR, Havens, JM, Necela, BM, Su, W, Chen, L, Yanagisawa, M, Anastasiadis, PZ, Guerra, R, Luxon, BA & Thompson, EA 2007, 'Functional genomic analysis reveals cross-talk between peroxisome proliferator-activated receptor γ and calcium signaling in human colorectal cancer cells', Journal of Biological Chemistry, vol. 282, no. 32, pp. 23387-23401. https://doi.org/10.1074/jbc.M702708200
    Bush, Craig R. ; Havens, Jennifer M. ; Necela, Brian M. ; Su, Weidong ; Chen, Lu ; Yanagisawa, Masahiro ; Anastasiadis, Panos Z. ; Guerra, Rudy ; Luxon, Bruce A. ; Thompson, E. Aubrey. / Functional genomic analysis reveals cross-talk between peroxisome proliferator-activated receptor γ and calcium signaling in human colorectal cancer cells. In: Journal of Biological Chemistry. 2007 ; Vol. 282, No. 32. pp. 23387-23401.
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    AU - Su, Weidong

    AU - Chen, Lu

    AU - Yanagisawa, Masahiro

    AU - Anastasiadis, Panos Z.

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    AU - Luxon, Bruce A.

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    AB - Activation of PPARγ in MOSER cells inhibits anchorage-dependent and anchorage-independent growth and invasion through Matrigel-coated transwell membranes. We carried out a longitudinal two-class microarray analysis in which mRNA abundance was measured as a function of time in cells treated with a thiazolidinedione PPARγ agonist or vehicle. A statistical machine learning algorithm that employs an empirical Bayesian implementation of the multivariate HotellingT2 score was used to identify differentially regulated genes. HotellingT2 scores, MB statistics, and maximum median differences were used as figures of merit to interrogate genomic ontology of these targets. Three major cohorts of genes were regulated: those involved in metabolism, DNA replication, and migration/motility, reflecting the cellular phenotype that attends activation of PPARγ. The bioinformatic analysis also inferred that PPARγ regulates calcium signaling. This response was unanticipated, because calcium signaling has not previously been associated with PPARγ activation. Ingenuity pathway analysis inferred that the nodal point in this cross-talk was Down syndrome critical region 1 (DSCR1). DSCR1 is an endogenous calcineurin inhibitor that blocks dephosphorylation and activation of members of the cytoplasmic component of nuclear factor of activated T cells transcription factors. Lentiviral short hairpin RNA-mediated knockdown of DSCR1 blocks PPARγ inhibition of proliferation and invasion, indicating that DSCR1 is required for suppression of transformed properties of early stage colorectal cancer cells by PPARγ. These data reveal a novel, heretofore unappreciated link between PPARγ and calcium signaling and indicate that DSCR1, which has previously been thought to function by suppression of the angiogenic response in endothelial cells, may also play a direct role in transformation of epithelial cells.

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