Natural compound PEITC inhibits gain of function of p53 mutants in cancer cells by switching YAP-binding partners between p53 and p73

Phenethyl isothiocyanate (PEITC) derived from cruciferous vegetables has shown anticancer activities by modulating apoptosis, cell cycle arrest, drug-metabolizing enzymes and even preferentially restoring a ‘WT-like’ conformation to p53^R175H. But its molecular anti-cancer mechanisms are not well understood. Evidence shows that switching YAP-binding partners from pro-tumorigenic to pro-apoptotic proteins might hold great potential for the treatment of human cancers harboring mtp53. In this study we investigated the impact of PEITC on mtp53-YAP-p73 interaction in cancers harboring a variety of p53 mutants, but not limited to structural mutations. We showed that breast cancer, colorectal and lung cancer cells harboring mtp53 (p53^R280K, p53^R273H) were more sensitive to PEITC than those cells harboring wtp53. We demonstrated that PEITC bound to YAP at its WW binding domain, and induced a conformational change, facilitated the dissociation of YAP-mtp53 complex and inhibited their pro-proliferative transcriptional activity in different cancer cells harboring mtp53. Concomitantly, PEITC acted as a molecular glue to enhance the association of YAP-p73 complex and induced apoptosis. These results provide insights into the anticancer activity of PEITC against a wide spectrum of cancers and highlight a unique mode of action for PEITC-based cancer therapy.