Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, University of Athens, 11527 Athens, Greece.
J Cell Biol. 2011 Dec 26;195(7):1123-40. doi: 10.1083/jcb.201108121.
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.
E-钙黏蛋白（CDH1）的丢失在癌变过程中经常发生，导致侵袭和转移。我们观察到，过度表达复制起始因子 Cdc6 的小鼠和人上皮细胞系发生了表型变化，具有间充质特征，并且 E-钙黏蛋白丢失。对各种类型的人类癌症的分析显示，Cdc6 表达增加与 E-钙黏蛋白水平降低之间存在强烈相关性。受这些发现的启发，我们发现 Cdc6 通过结合其启动子的 E 盒来抑制 CDH1 转录，导致染色体绝缘子 CTCF 解离、组蛋白变体 H2A.Z 置换和启动子异染色质化。突变分析确定了 Cdc6 的 Walker B 基序和 C 末端区域对于 CDH1 转录抑制是必需的。引人注目的是，CTCF 的置换导致相邻复制起始点的激活。这些数据表明，Cdc6 作为 E-钙黏蛋白基因座的分子开关，将转录抑制与复制激活联系起来，并提供了一个很好的例子，说明复制起始因子如何篡夺替代程序来完成不同的细胞功能。
