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

Abstract

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.

• Authors: Fotini Vogiatzi, Dominique T Brandt, Jean Schneikert, Jeannette Fuchs, Katharina Grikscheit, Michael Wanzel, Evangelos Pavlakis, Joël P Charles, Oleg Timofeev, Andrea Nist, Marco Mernberger, Eva J Kantelhardt, Udo Siebolts, Frank Bartel, Ralf Jacob, Ariane Rath, Roland Moll, Robert Grosse, Thorsten Stiewe
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 113 Issue 52 Pg. E8433-E8442 (12 27 2016) ISSN: 1091-6490 [Electronic] United States
• PMID: 27956623 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Calreticulin
• Glycoproteins
• Mutant Proteins
• Oncogene Proteins
• RNA, Small Interfering
• Sp1 Transcription Factor
• Sp1 protein, human
• TP53 protein, human
• Tumor Suppressor Protein p53
• Calnexin
• ENTPD5 protein, human
• Pyrophosphatases

Topics

• Animals
• Apoptosis
• Calnexin (metabolism)
• Calreticulin (metabolism)
• Carcinogenesis (metabolism)
• Cell Line, Tumor
• Disease Progression
• Endoplasmic Reticulum (metabolism)
• Female
• Glycoproteins (metabolism)
• Glycosylation
• Humans
• Male
• Mice
• Mutant Proteins (genetics, physiology)
• Mutation
• Neoplasm Invasiveness
• Neoplasm Metastasis
• Oncogene Proteins (metabolism)
• Prognosis
• Pyrophosphatases (metabolism)
• RNA Interference
• RNA, Small Interfering (metabolism)
• Sp1 Transcription Factor (metabolism)
• Tumor Suppressor Protein p53 (genetics, physiology)