TY - JOUR
T1 - Epigenetic mechanisms underlying the dynamic expression of cancer-testis genes, PAGE2,-2B and SPANX-B, during mesenchymal-to-epithelial transition
AU - Yilmaz-Ozcan, Sinem
AU - Sade, Asli
AU - Kucukkaraduman, Baris
AU - Kaygusuz, Yasemin
AU - Senses, Kerem Mert
AU - Banerjee, Sreeparna
AU - Gure, Ali Osmay
N1 - Publisher Copyright:
© 2014 Yilmaz-Ozcan et al.
PY - 2014/9/17
Y1 - 2014/9/17
N2 - 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-toepithelial 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.
AB - 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-toepithelial 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.
UR - http://www.scopus.com/inward/record.url?scp=84907212861&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0107905
DO - 10.1371/journal.pone.0107905
M3 - Article
C2 - 25229454
AN - SCOPUS:84907212861
SN - 1932-6203
VL - 9
JO - PLoS ONE
JF - PLoS ONE
IS - 9
M1 - e107905
ER -
