title: CDX2 homeoprotein is involved in the regulation of ST6GalNAc-I gene in intestinal metaplasia.
abstract: De novo expression of Sialyl-Tn (STn) antigen is one of the most common features of intestinal metaplasia (IM) and gastric carcinomas, and its biosynthesis has been mostly attributed to ST6GalNAc-I activity. However, the regulation of this glycosyltransferase expression is not elucidated. In IM lesions and in the intestine, CDX2 homeobox transcription factor is co-expressed with STn and ST6GalNAc-I. We therefore hypothesized that CDX2 might induce STn expression by positive regulation of ST6GalNAc-I. We showed that ST6GalNAc-I transcript levels and CDX2 have a coordinated expression upon Caco-2 in vitro differentiation, and overexpression of CDX2 in MKN45 gastric cells increases ST6GalNAc-I transcript levels. Nine putative CDX-binding sites in the ST6GalNAc-I-regulatory sequence were identified and analyzed by chromatin immunoprecipitation in Caco-2 cells and in IM. The results showed that CDX2 protein is recruited to all regions, being the most proximal sites preferentially occupied in vivo. Luciferase assays demonstrated that CDX2 is able to transactivate ST6GalNac-I-regulatory region. The induction was stronger for the regions mapped in the neighbourhood of ATG start codon and site-directed mutagenesis of these sites confirmed their importance. In conclusion, we show that CDX2 transcriptionally regulates ST6GalNAc-I gene expression, specifically in the preneoplastic IM lesion.
authors: 1] Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal [2] Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal [3] Faculty of Medicine, University of Porto, Porto, Portugal.
authors: Rita
authors: R
authors: Pinto
authors: 1] Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal [2] Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal.
authors: Rita
authors: R
authors: Barros
authors: Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal.
authors: Isabel
authors: I
authors: Pereira-Castro
authors: Instituto Nacional de Investigação Agrária e Veterinária, Quinta da Fonte Boa, Vale de Santarém, Portugal.
authors: Patricia
authors: P
authors: Mesquita
authors: ICAAM, Universidade de Évora, Évora, Portugal.
authors: Luis T
authors: LT
authors: da Costa
authors: Copenhagen Center for Glycomics, Departments of Cellular and Molecular Medicine, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
authors: Eric P
authors: EP
authors: Bennett
authors: 1] Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal [2] Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal [3] Faculty of Medicine, University of Porto, Porto, Portugal [4] Department of Biology, Faculty of Sciences, University of Porto, Porto, Portugal.
authors: Raquel
authors: R
authors: Almeida
authors: 1] Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal [2] Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal [3] Faculty of Medicine, University of Porto, Porto, Portugal.
authors: Leonor
authors: L
authors: David
mesh_terms: D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D001483:Base Sequence; D000071616:CDX2 Transcription Factor; D018938:Caco-2 Cells; D002454:Cell Differentiation; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D007410:Intestinal Diseases / Q000378:metabolism*; D008679:Metaplasia / Q000378:metabolism; D008969:Molecular Sequence Data; D011230:Precancerous Conditions / Q000378:metabolism*; D012045:Regulatory Sequences, Nucleic Acid; D012799:Sialyltransferases / Q000235:genetics / Q000378:metabolism*; D000094802:beta-D-Galactoside alpha 2-6-Sialyltransferase
chemical_list: D015703:Antigens, CD; D000071616:CDX2 Transcription Factor; D018398:Homeodomain Proteins; D012799:Sialyltransferases; C491270:CDX2 protein, human; C093493:ST6GAL1 protein, human; D000094802:beta-D-Galactoside alpha 2-6-Sialyltransferase