A "Twist box" code of p53 inactivation in sarcomas

Twist1, a bHLH transcriptional factor, plays a critical role in mesoderm development. Twist1 is overexpressed in several tumor types where it has been shown to affect several oncogenic processes (e.g. apoptosis, senescence, stemness and epithelial-mesenchymal transition), but the mechanism of action of this embryonic transcription factor in cancer is poorly defined. In particular, the laboratory where I work has demonstrated that Twist1 antagonizes oncogene-induced apoptosis and senescence at least in part by interfering with the ARF/p53 pathway. However, we recently collected data that Twist1 interferes with p53 also independently of ARF. By investigating the role of Twist1 in sarcomas, we found that Twist1 interacts directly with p53. As a result of this interaction, Twist1 hinders key phosphorylations of p53, thus facilitating MDM2:p53 complex formation and p53 degradation. Our study suggests the existence of a “Twist code” for p53 inactivation in sarcomas and discloses the possibility that targeting of Twist1:p53 interaction might provide novel therapeutic strategies for these tumors.