Aprotein that permits cells to replicate their DNA also shuts down a tumor suppressor gene, Sideridou et al. report.
The cell adhesion molecule E-cadherin is a cancer fighter that is mutated in many tumors. In previous work, the researchers uncovered a possible link between E-cadherin and Cdc6, a protein that belongs to a complex that licenses DNA replication. Cells typically produce Cdc6 only for a brief period of time, destroying it to prevent their DNA from duplicating more than once per cell cycle. The researchers found that abnormal overproduction of Cdc6 led to a phenomenon called epithelial to mesenchymal transition (EMT). Cells that jettison E-cadherin often undergo EMT, a process that takes place during embryogenesis but that cancer cells also use to spur metastasis.
In the new study, Sideridou et al. found that Cdc6 attaches to the promoter of the E-cadherin gene and turns off its expression. Cdc6 binding triggered the promoter's conversion into heterochromatin, expelling the H2A.Z histone that prevents gene silencing and ejecting CTCF, a chromosomal insulator that allows gene expression. This chromatin remodeling was accompanied by activation of nearby replication origins, sites where DNA duplication begins. Thus, this work indicates that Cdc6 overproduction may aid cancer cells in two ways: by shuttering an antitumor gene and by sparking DNA replication. An unanswered question is what other genes Cdc6 overexpression influences in tumor cells.
