Naslov
Cdc6 expression represses E-cadherin transcription and activates adjacent replication origins

Autori
Sideridou, Maria ; Zakopoulou, Roubini ; Evangelou, Konstantinos ; Liontos, Michalis ; Kotsinas, Athanassios ; Rampakakis, Emmanouil ; Gagos, Sarantis ; Kahata, Kaoru ; Grabušić, Kristina ; Gkouskou, Kalliopi ; Trougakos, Ioannis P. ; Kolettas, Evangelos ; Georgakilas, Alexandros G. ; Volarević, Siniša ; Eliopoulos, Aristides G. ; Zannis-Hadjopoulos, Maria ; Moustakas, Aristidis ; Gorgoulis, Vassilis G.

Izvornik
The Journal of cell biology (0021-9525) 195 (2011), 7; 1123-1140

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
carcinogenesis; Cdc6; E-cadherin

Sažetak
E-cadherin (CDH1) loss occurs frequently in carcinogenesis contributing to invasion and metastasis. We observed that mouse and human epithelial cell lines overexpressing the replication licensing factor Cdc6 undergo phenotypic changes with mesenchymal features and loss of E-cadherin. Analysis in various types of human cancer revealed a strong correlation between increased Cdc6 expression and reduced E-cadherin levels. Prompted by these findings, we discovered that Cdc6 represses CDH1 transcription by binding to the E-boxes of its promoter, leading to dissociation of the chromosomal insulator CTCF, displacement of the histone variant H2A.Z and promoter heterochromatinization. Mutation analysis identified the Walker-B motif and C-terminal region of Cdc6 being essential for CDH1 transcriptional suppression. Strikingly, CTCF displacement results in activation of adjacent origins of replication. These data demonstrate that Cdc6 acts as a molecular switch at the E-cadherin locus linking transcriptional repression to activation of replication and provide a telling example of how replication licensing factors could usurp alternative programs to fulfill distinct cellular functions.

Izvorni jezik
Engleski

Znanstvena područja
Temeljne medicinske znanosti

POVEZANOST RADA