Cdc6 expression represses E-cadherin transcription and activates adjacent replication origins.
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 underwent 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 repressed 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. Mutational analysis identified the Walker B motif and C-terminal region of Cdc6 as essential for CDH1 transcriptional suppression. Strikingly, CTCF displacement resulted 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.
Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, University of Athens, 11527 Athens, Greece.
Maria
M
Sideridou
Roubini
R
Zakopoulou
Konstantinos
K
Evangelou
Michalis
M
Liontos
Athanassios
A
Kotsinas
Emmanouil
E
Rampakakis
Sarantis
S
Gagos
Kaoru
K
Kahata
Kristina
K
Grabusic
Kalliopi
K
Gkouskou
Ioannis P
IP
Trougakos
Evangelos
E
Kolettas
Alexandros G
AG
Georgakilas
Sinisa
S
Volarevic
Aristides G
AG
Eliopoulos
Maria
M
Zannis-Hadjopoulos
Aristidis
A
Moustakas
Vassilis G
VG
Gorgoulis
D020816:Amino Acid Motifs; D000818:Animals; D015703:Antigens, CD; D000076246:CCCTC-Binding Factor; D015820:Cadherins / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D002460:Cell Line; D004247:DNA / Q000235:genetics*; D004261:DNA Replication / Q000235:genetics*; D004285:Dogs; D015536:Down-Regulation; D006657:Histones / Q000378:metabolism; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D009857:Oncogenes / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics*
D015703:Antigens, CD; D000076246:CCCTC-Binding Factor; C103706:CDC6 protein, human; C513384:CDH1 protein, human; C000619697:CTCF protein, human; D015820:Cadherins; D018797:Cell Cycle Proteins; C000619698:Ctcf protein, mouse; D006657:Histones; D009687:Nuclear Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; D004247:DNA