Mutant p53 promotes tumor progression and metastasis by the endoplasmic reticulum UDPase ENTPD5

Significance p53 mutations are the most frequent genetic alteration in cancer and are often indicative of poor patient survival prognosis. The most prevalent missense mutations lead to a “gain of function” (GOF) that actively drives tumor progression, metastasis, and therapy resistance. Our study links the mutant p53 (mutp53) GOF to enhanced N-glycoprotein folding via ectonucleoside triphosphate diphosphohydrolase 5 (ENTPD5) in the calnexin/calreticulin cycle of the endoplasmic reticulum. Mutp53 thus increases expression of prometastatic cell surface proteins, such as receptors and integrins, not only quantitatively but also qualitatively, with respect to N-glycosylation state. Our study reveals N-glycoprotein quality control in the endoplasmic reticulum as an indispensable mechanism underlying the progression of tumors with GOF mutp53 that could provide new possibilities for treating prognostically challenging p53-mutated cancers. Mutations in the p53 tumor suppressor gene are the most frequent genetic alteration in cancer and are often associated with progression from benign to invasive stages with metastatic potential. Mutations inactivate tumor suppression by p53, and some endow the protein with novel gain of function (GOF) properties that actively promote tumor progression and metastasis. By comparative gene expression profiling of p53-mutated and p53-depleted cancer cells, we identified ectonucleoside triphosphate diphosphohydrolase 5 (ENTPD5) as a mutant p53 target gene, which functions as a uridine 5′-diphosphatase (UDPase) in the endoplasmic reticulum (ER) to promote the folding of N-glycosylated membrane proteins. A comprehensive pan-cancer analysis revealed a highly significant correlation between p53 GOF mutations and ENTPD5 expression. Mechanistically, mutp53 is recruited by Sp1 to the ENTPD5 core promoter to induce its expression. We show ENTPD5 to be a mediator of mutant p53 GOF activity in clonogenic growth, architectural tissue remodeling, migration, invasion, and lung colonization in an experimental metastasis mouse model. Our study reveals folding of N-glycosylated membrane proteins in the ER as a mechanism underlying the metastatic progression of tumors with mutp53 that could provide new possibilities for cancer treatment.