Integrin α6β4 controls the expression of genes associated with cell motility, invasion, and metastasis, including S100A4/metastasin

Min Chen, Mala Sinha, Bruce A. Luxon, Anne R. Bresnick, Kathleen L. O'Connor

    Research output: Contribution to journalArticle

    104 Citations (Scopus)

    Abstract

    The integrin α6β4 is associated with carcinoma progression by contributing to apoptosis resistance, invasion, and metastasis, due in part to the activation of select transcription factors. To identify genes regulated by the α6β4 integrin, we compared gene expression profiles of MDA-MB-435 cells that stably express integrin α6β4 (MDA/β4) and vector-only-transfected cells (MDA/mock) using Affymetrix GeneChip® analysis. Our results show that integrin α6β4 altered the expression of 538 genes (p < 0.01). Of these genes, 36 are associated with pathways implicated in cell motility and metastasis, including S100A4/metastasin. S100A4 expression correlated well with integrin α6β4 expression in established cell lines. Suppression of S100A4 by small interference RNA resulted in a reduced capacity of 6/34-expressing cells to invade a reconstituted basement membrane in response to lysophosphatidic acid. Using small interference RNA, promoter analysis, and chromatin immunoprecipitation, we demonstrate that S100A4 is regulated by NFAT5, thus identifying the first target of NFAT5 in cancer. In addition, several genes that are known to be regulated by DNA methylation were up-regulated dramatically by integrin α6β4 expression, including S100A4, FST, PDLIM4, CAPG, and Nkx2.2. Notably, inhibition of DNA methyltransferases stimulated expression of these genes in cells lacking the α6β4 integrin, whereas demethylase inhibitors suppressed expression in α6β4 integrin-expressing cells. Alterations in DNA methylation were confirmed by bisulfate sequencing, thus suggesting that integrin α6β4 signaling can lead to the demethylation of select promoters. In summary, our data suggest that integrin α6β4 confers a motile and invasive phenotype to breast carcinoma cells by regulating proinvasive and prometastatic gene expression.

    Original languageEnglish (US)
    Pages (from-to)1484-1494
    Number of pages11
    JournalJournal of Biological Chemistry
    Volume284
    Issue number3
    DOIs
    StatePublished - Jan 16 2009

    Fingerprint

    Integrins
    Cell Movement
    Genes
    Neoplasm Metastasis
    Gene Expression
    DNA Methylation
    RNA Interference
    Gene expression
    Cells
    RNA
    Chromatin Immunoprecipitation
    Methyltransferases
    Transcriptome
    Basement Membrane
    Chromatin
    Transcription Factors
    Chemical activation
    Apoptosis
    Breast Neoplasms
    Carcinoma

    ASJC Scopus subject areas

    • Biochemistry
    • Cell Biology
    • Molecular Biology

    Cite this

    Integrin α6β4 controls the expression of genes associated with cell motility, invasion, and metastasis, including S100A4/metastasin. / Chen, Min; Sinha, Mala; Luxon, Bruce A.; Bresnick, Anne R.; O'Connor, Kathleen L.

    In: Journal of Biological Chemistry, Vol. 284, No. 3, 16.01.2009, p. 1484-1494.

    Research output: Contribution to journalArticle

    Chen, Min ; Sinha, Mala ; Luxon, Bruce A. ; Bresnick, Anne R. ; O'Connor, Kathleen L. / Integrin α6β4 controls the expression of genes associated with cell motility, invasion, and metastasis, including S100A4/metastasin. In: Journal of Biological Chemistry. 2009 ; Vol. 284, No. 3. pp. 1484-1494.
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    abstract = "The integrin α6β4 is associated with carcinoma progression by contributing to apoptosis resistance, invasion, and metastasis, due in part to the activation of select transcription factors. To identify genes regulated by the α6β4 integrin, we compared gene expression profiles of MDA-MB-435 cells that stably express integrin α6β4 (MDA/β4) and vector-only-transfected cells (MDA/mock) using Affymetrix GeneChip{\circledR} analysis. Our results show that integrin α6β4 altered the expression of 538 genes (p < 0.01). Of these genes, 36 are associated with pathways implicated in cell motility and metastasis, including S100A4/metastasin. S100A4 expression correlated well with integrin α6β4 expression in established cell lines. Suppression of S100A4 by small interference RNA resulted in a reduced capacity of 6/34-expressing cells to invade a reconstituted basement membrane in response to lysophosphatidic acid. Using small interference RNA, promoter analysis, and chromatin immunoprecipitation, we demonstrate that S100A4 is regulated by NFAT5, thus identifying the first target of NFAT5 in cancer. In addition, several genes that are known to be regulated by DNA methylation were up-regulated dramatically by integrin α6β4 expression, including S100A4, FST, PDLIM4, CAPG, and Nkx2.2. Notably, inhibition of DNA methyltransferases stimulated expression of these genes in cells lacking the α6β4 integrin, whereas demethylase inhibitors suppressed expression in α6β4 integrin-expressing cells. Alterations in DNA methylation were confirmed by bisulfate sequencing, thus suggesting that integrin α6β4 signaling can lead to the demethylation of select promoters. In summary, our data suggest that integrin α6β4 confers a motile and invasive phenotype to breast carcinoma cells by regulating proinvasive and prometastatic gene expression.",
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    AU - O'Connor, Kathleen L.

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