Cytolethal Distending Toxin-Increased DNA Damage and Ploidy Involve the YAP/TAZ-TEAD Signaling Pathway.

Abstract

The bacterial genotoxins cytolethal distending toxin (CDT) and colibactin cause severe DNA damage in host cells and impair the DNA-damage response, leading to genomic instability. Some phenotypes induced by these genotoxins (actin cytoskeleton remodeling, stress fibers accumulation, disturbance of focal adhesion, cell-cell junctions' disassembly, increased ploidy and genome instability, and endoreplication) are known to involve the Hippo signaling pathway, suggesting a link between some effects induced by these toxins and Hippo pathway. We investigated the Hippo signaling pathway in normal and cancer-derived epithelial intestinal and hepatic cell lines following intoxication with CDT/CdtB and colibactin. We have shown that the active CdtB subunit of CDT modulates the expression of transcripts and proteins of the Hippo downstream central transcriptional coactivators YAP/TAZ. CdtB exposure drove increased TEAD-mediated transcription, confirmed by the upregulation of direct TEAD target genes. Inhibition of the YAP/TAZ binding to TEADs (verteporfin and K-975) dampened the effects of CdtB, particularly DNA damage and repair, and increased ploidy. These findings suggest that YAP/TAZ-TEAD signaling is involved in increased ploidy in cells surviving the DNA damage induced by CDT/CdtB. In addition, exposure to colibactin, a genotoxic metabolite produced by Escherichia coli, induced similar effects. Overall, these data show that infection with genotoxin-producing bacteria involves the YAP/TAZ-TEAD signaling pathway to control ploidy following DNA damage in epithelial cells.