Tummala, Krishna SGomes, Ana LYilmaz, MahmutGraña, OsvaldoBakiri, LatifaRuppen, IsabelXiménez-Embún, PilarSheshappanavar, VinayataRodriguez-Justo, ManuelPisano, David GWagner, Erwin FDjouder, Nabil2024-02-082024-02-082014-12-08Cancer Cell . 2014 ;26(6):826-839.http://hdl.handle.net/20.500.12105/17547Molecular 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.engVoRhttp://creativecommons.org/licenses/by-nc-nd/4.0/DNA DamageAnimalsCarcinoma, HepatocellularDiethylnitrosamineGene Expression Regulation, NeoplasticHepatocytesHumansAttribution-NonCommercial-NoDerivatives 4.0 Internacional2545390126682610.1016/j.ccell.2014.10.0021878-3686Cancer cellopen access