title: Inhibition of de novo NAD(+) synthesis by oncogenic URI causes liver tumorigenesis through DNA damage.
abstract: Molecular mechanisms responsible for hepatocellular carcinoma (HCC) remain largely unknown. Using genetically engineered mouse models, we show that hepatocyte-specific expression of unconventional prefoldin RPB5 interactor (URI) leads to a multistep process of HCC development, whereas its genetic reduction in hepatocytes protects against diethylnitrosamine (DEN)-induced HCC. URI inhibits aryl hydrocarbon (AhR)- and estrogen receptor (ER)-mediated transcription of enzymes implicated in L-tryptophan/kynurenine/nicotinamide adenine dinucleotide (NAD(+)) metabolism, thereby causing DNA damage at early stages of tumorigenesis. Restoring NAD(+) pools with nicotinamide riboside (NR) prevents DNA damage and tumor formation. Consistently, URI expression in human HCC is associated with poor survival and correlates negatively with L-tryptophan catabolism pathway. Our results suggest that boosting NAD(+) can be prophylactic or therapeutic in HCC.
authors.affiliation: Growth Factors, Nutrients and Cancer Group, BBVA Foundation-Cancer Cell Biology Programme, Spanish National Cancer Research Centre, CNIO, 28029 Madrid, Spain.
authors.forename: Krishna S
authors.initials: KS
authors.lastname: Tummala
authors.affiliation: Growth Factors, Nutrients and Cancer Group, BBVA Foundation-Cancer Cell Biology Programme, Spanish National Cancer Research Centre, CNIO, 28029 Madrid, Spain.
authors.forename: Ana L
authors.initials: AL
authors.lastname: Gomes
authors.affiliation: Growth Factors, Nutrients and Cancer Group, BBVA Foundation-Cancer Cell Biology Programme, Spanish National Cancer Research Centre, CNIO, 28029 Madrid, Spain.
authors.forename: Mahmut
authors.initials: M
authors.lastname: Yilmaz
authors.affiliation: Bioinformatics Unit, Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre, CNIO, 28029 Madrid, Spain.
authors.forename: Osvaldo
authors.initials: O
authors.lastname: Graña
authors.affiliation: Genes, Development, and Disease Group, BBVA Foundation-Cancer Cell Biology Programme, Spanish National Cancer Research Centre, CNIO, 28029 Madrid, Spain.
authors.forename: Latifa
authors.initials: L
authors.lastname: Bakiri
authors.affiliation: Proteomics Core Unit, ProteoRed ISCIII, Biotechnology Programme, Spanish National Cancer Research Centre, CNIO, 28029 Madrid, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Ruppen
authors.affiliation: Proteomics Core Unit, ProteoRed ISCIII, Biotechnology Programme, Spanish National Cancer Research Centre, CNIO, 28029 Madrid, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Ximénez-Embún
authors.affiliation: Department of Pathology, Royal London Hospital, London E1 1BB, UK.
authors.forename: Vinayata
authors.initials: V
authors.lastname: Sheshappanavar
authors.affiliation: Department of Cellular Pathology, University College London NHS Trust, London NW1 2BU, UK.
authors.forename: Manuel
authors.initials: M
authors.lastname: Rodriguez-Justo
authors.affiliation: Bioinformatics Unit, Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre, CNIO, 28029 Madrid, Spain.
authors.forename: David G
authors.initials: DG
authors.lastname: Pisano
authors.affiliation: Genes, Development, and Disease Group, BBVA Foundation-Cancer Cell Biology Programme, Spanish National Cancer Research Centre, CNIO, 28029 Madrid, Spain.
authors.forename: Erwin F
authors.initials: EF
authors.lastname: Wagner
authors.affiliation: Growth Factors, Nutrients and Cancer Group, BBVA Foundation-Cancer Cell Biology Programme, Spanish National Cancer Research Centre, CNIO, 28029 Madrid, Spain. Electronic address: ndjouder@cnio.es.
authors.forename: Nabil
authors.initials: N
authors.lastname: Djouder
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology*; D004249:DNA Damage; D004052:Diethylnitrosamine; D015972:Gene Expression Regulation, Neoplastic; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology*; D008114:Liver Neoplasms, Experimental; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009243:NAD / Q000378:metabolism*; D040901:Proteomics; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D012097:Repressor Proteins; C117184:URI1 protein, human; C485517:Uri1 protein, mouse; D009243:NAD; D004052:Diethylnitrosamine