title: 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.affiliation: Institute of Molecular Oncology, Philipps-University, 35043 Marburg, Germany.
authors.forename: Fotini
authors.initials: F
authors.lastname: Vogiatzi
authors.affiliation: Institute of Pharmacology, Philipps-University, 35032 Marburg, Germany.
authors.forename: Dominique T
authors.initials: DT
authors.lastname: Brandt
authors.affiliation: Institute of Molecular Oncology, Philipps-University, 35043 Marburg, Germany.
authors.forename: Jean
authors.initials: J
authors.lastname: Schneikert
authors.affiliation: Institute of Molecular Oncology, Philipps-University, 35043 Marburg, Germany.
authors.forename: Jeannette
authors.initials: J
authors.lastname: Fuchs
authors.affiliation: Institute of Pharmacology, Philipps-University, 35032 Marburg, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Grikscheit
authors.affiliation: Institute of Molecular Oncology, Philipps-University, 35043 Marburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Wanzel
authors.affiliation: Institute of Molecular Oncology, Philipps-University, 35043 Marburg, Germany.
authors.forename: Evangelos
authors.initials: E
authors.lastname: Pavlakis
authors.affiliation: Institute of Molecular Oncology, Philipps-University, 35043 Marburg, Germany.
authors.forename: Joël P
authors.initials: JP
authors.lastname: Charles
authors.affiliation: Institute of Molecular Oncology, Philipps-University, 35043 Marburg, Germany.
authors.forename: Oleg
authors.initials: O
authors.lastname: Timofeev
authors.affiliation: Genomics Core Facility, Philipps-University, 35043 Marburg, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Nist
authors.affiliation: Institute of Molecular Oncology, Philipps-University, 35043 Marburg, Germany.|Genomics Core Facility, Philipps-University, 35043 Marburg, Germany.
authors.forename: Marco
authors.initials: M
authors.lastname: Mernberger
authors.affiliation: Clinic of Gynecology, Faculty of Medicine, Martin-Luther-University Halle Wittenberg, 06097 Halle/Saale, Germany.
authors.forename: Eva J
authors.initials: EJ
authors.lastname: Kantelhardt
authors.affiliation: Institute of Pathology, Faculty of Medicine, Martin-Luther-University Halle-Wittenberg, 06112 Halle/Saale, Germany.
authors.forename: Udo
authors.initials: U
authors.lastname: Siebolts
authors.affiliation: Institute of Pathology, Faculty of Medicine, Martin-Luther-University Halle-Wittenberg, 06112 Halle/Saale, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Bartel
authors.affiliation: Department of Cell Biology and Cell Pathology, Philipps-University, 35037 Marburg, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Jacob
authors.affiliation: Institute of Pathology, Philipps-University, 35043 Marburg, Germany.
authors.forename: Ariane
authors.initials: A
authors.lastname: Rath
authors.affiliation: Institute of Pathology, Philipps-University, 35043 Marburg, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Moll
authors.affiliation: Institute of Pharmacology, Philipps-University, 35032 Marburg, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Grosse
authors.affiliation: Institute of Molecular Oncology, Philipps-University, 35043 Marburg, Germany; thorsten.stiewe@uni-marburg.de.|Genomics Core Facility, Philipps-University, 35043 Marburg, Germany.|German Center for Lung Research (DZL), Universities of Giessen and Marburg Lung Center, 35392 Giessen, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Stiewe
mesh_terms: D000818:Animals; D017209:Apoptosis; D037281:Calnexin / Q000378:metabolism; D037282:Calreticulin / Q000378:metabolism; D063646:Carcinogenesis / Q000378:metabolism; D045744:Cell Line, Tumor; D018450:Disease Progression; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005260:Female; D006023:Glycoproteins / Q000378:metabolism; D006031:Glycosylation; D006801:Humans; D008297:Male; D051379:Mice; D050505:Mutant Proteins / Q000235:genetics / Q000502:physiology; D009154:Mutation; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D015513:Oncogene Proteins / Q000378:metabolism*; D011379:Prognosis; D011755:Pyrophosphatases / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D016329:Sp1 Transcription Factor / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000502:physiology*
chemical_list: D037282:Calreticulin; D006023:Glycoproteins; D050505:Mutant Proteins; D015513:Oncogene Proteins; D034741:RNA, Small Interfering; D016329:Sp1 Transcription Factor; C108209:SP1 protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D037281:Calnexin; C117634:ENTPD5 protein, human; D011755:Pyrophosphatases
keywords: ENTPD5; N-glycosylation; metastasis; p53; tumor suppressor