A “Twist box” Code of p53 Inactivation: Twist box:p53 Interaction Promotes p53 Degradation

SummaryTwist proteins have been shown to contribute to cancer development and progression by impinging on different regulatory pathways, but their mechanism of action is poorly defined. By investigating the role of Twist in sarcomas, we found that Twist1 acts as a mechanism alternative to TP53 mutation and MDM2 overexpression to inactivate p53 in mesenchymal tumors. We provide evidence that Twist1 binds p53 C terminus through the Twist box. This interaction hinders key posttranslational modifications of p53 and facilitates its MDM2-mediated degradation. Our study suggests the existence of a Twist box code of p53 inactivation and provides the proof of principle that targeting the Twist box:p53 interaction might offer additional avenues for cancer treatment.

► Twist1 is overexpressed in p53 wild-type/MDM2-negative sarcomas
► Different from EMT, Twist1 inhibits p53 also via an E-box-independent mechanism
► Twist interacts with the p53 C-terminal regulatory domain through the Twist box
► Twist1 hinders p53 Ser392 phosphorylation and facilitates p53 degradation