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

Area of Science:

• Molecular biology
• Cancer research
• Epigenetics

Background:

• E-cadherin (CDH1) loss is a hallmark of cancer progression, promoting invasion and metastasis.
• The replication licensing factor Cdc6 is implicated in cell cycle regulation.

Purpose of the Study:

• To investigate the role of Cdc6 in E-cadherin regulation during carcinogenesis.
• To elucidate the molecular mechanisms by which Cdc6 affects CDH1 transcription.

Main Methods:

• Overexpression of Cdc6 in epithelial cell lines.
• Analysis of human cancer samples for Cdc6 and E-cadherin correlation.
• Chromatin immunoprecipitation assays to study protein-DNA interactions.
• Reporter assays to assess promoter activity.
• Mutational analysis of Cdc6.

Main Results:

• Cdc6 overexpression induced mesenchymal features and E-cadherin loss in epithelial cells.
• Increased Cdc6 expression strongly correlated with reduced E-cadherin levels in human cancers.
• Cdc6 directly repressed CDH1 transcription by binding to promoter E-boxes.
• This repression involved CTCF dissociation, H2A.Z displacement, and heterochromatin formation.
• Cdc6 mutations in the Walker B motif or C-terminus abolished CDH1 repression.
• CTCF displacement by Cdc6 activated adjacent replication origins.

Conclusions:

• Cdc6 acts as a molecular switch at the E-cadherin locus, linking transcriptional repression to replication activation.
• Replication licensing factors can adopt alternative functions in cellular processes like carcinogenesis.
• Cdc6-mediated E-cadherin repression offers a potential therapeutic target in cancer treatment.