Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 113, Issue 52, Pages E8433-E8442Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1612711114
Keywords
p53; tumor suppressor; ENTPD5; N-glycosylation; metastasis
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Funding
- Deutsche Forschungsgemeinschaft [DFG TRR81, KFO210, STI 182/7-1]
- European Research Council
- Bundesministerium fur Bildung und Forschung
- Rhon Klinikum AG
- German Center for Lung Research
- Deutsche Jose Carreras Leukamie-Stiftung
- Deutsche Krebshilfe [111250, 111444]
- Universities of Giessen and Marburg Lung Center
- Von-Behring-Rontgen-Stiftung
- Universitatsklinikum Giessen und Marburg
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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 ectonucleo-side 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.
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