title: Epigenetic mechanisms underlying the dynamic expression of cancer-testis genes, PAGE2, -2B and SPANX-B, during mesenchymal-to-epithelial transition.
abstract: Cancer-testis (CT) genes are expressed in various cancers but not in normal tissues other than in cells of the germline. Although DNA demethylation of promoter-proximal CpGs of CT genes is linked to their expression in cancer, the mechanisms leading to demethylation are unknown. To elucidate such mechanisms we chose to study the Caco-2 colorectal cancer cell line during the course of its spontaneous differentiation in vitro, as we found CT genes, in particular PAGE2, -2B and SPANX-B, to be up-regulated during this process. Differentiation of these cells resulted in a mesenchymal-to-epithelial transition (MET) as evidenced by the gain of epithelial markers CDX2, Claudin-4 and E-cadherin, and a concomitant loss of mesenchymal markers Vimentin, Fibronectin-1 and Transgelin. PAGE2 and SPAN-X up-regulation was accompanied by an increase in Ten-eleven translocation-2 (TET2) expression and cytosine 5-hydroxymethylation as well as the disassociation of heterochromatin protein 1 and the polycomb repressive complex 2 protein EZH2 from promoter-proximal regions of these genes. Reversal of differentiation resulted in down-regulation of PAGE2, -2B and SPANX-B, and induction of epithelial-to-mesenchymal transition (EMT) markers, demonstrating the dynamic nature of CT gene regulation in this model.
authors.affiliation: Department of Molecular Biology and Genetics, Bilkent University, Ankara, Turkey.
authors.forename: Sinem
authors.initials: S
authors.lastname: Yilmaz-Ozcan
authors.affiliation: Department of Biological Sciences, Middle East Technical University, Ankara, Turkey.
authors.forename: Asli
authors.initials: A
authors.lastname: Sade
authors.affiliation: Department of Molecular Biology and Genetics, Bilkent University, Ankara, Turkey.
authors.forename: Baris
authors.initials: B
authors.lastname: Kucukkaraduman
authors.affiliation: Department of Molecular Biology and Genetics, Bilkent University, Ankara, Turkey.
authors.forename: Yasemin
authors.initials: Y
authors.lastname: Kaygusuz
authors.affiliation: Department of Molecular Biology and Genetics, Bilkent University, Ankara, Turkey.
authors.forename: Kerem Mert
authors.initials: KM
authors.lastname: Senses
authors.affiliation: Department of Biological Sciences, Middle East Technical University, Ankara, Turkey.
authors.forename: Sreeparna
authors.initials: S
authors.lastname: Banerjee
authors.affiliation: Department of Molecular Biology and Genetics, Bilkent University, Ankara, Turkey.
authors.forename: Ali Osmay
authors.initials: AO
authors.lastname: Gure
mesh_terms: D000951:Antigens, Neoplasm / Q000235:genetics*; D002454:Cell Differentiation / Q000235:genetics; D045744:Cell Line, Tumor; D054338:Cell Transdifferentiation / Q000235:genetics*; D000090266:Chromobox Protein Homolog 5; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D049308:Dioxygenases; D000071221:Enhancer of Zeste Homolog 2 Protein; D044127:Epigenesis, Genetic; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics*; D063151:Polycomb Repressive Complex 2 / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000378:metabolism
chemical_list: D000951:Antigens, Neoplasm; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C000603522:PAGE2 protein, human; D011518:Proto-Oncogene Proteins; C518957:SPANXB1 protein, human; D000090266:Chromobox Protein Homolog 5; D049308:Dioxygenases; C541081:TET2 protein, human; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2