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.