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: Krishna S Tummala, Ana L Gomes, Mahmut Yilmaz, Osvaldo Graña, Latifa Bakiri, Isabel Ruppen, Pilar Ximénez-Embún, Vinayata Sheshappanavar, Manuel Rodriguez-Justo, David G Pisano, Erwin F Wagner, Nabil Djouder
• Journal: Cancer cell (Cancer Cell) Vol. 26 Issue 6 Pg. 826-839 (Dec 08 2014) ISSN: 1878-3686 [Electronic] United States
• PMID: 25453901 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• Intracellular Signaling Peptides and Proteins
• Repressor Proteins
• URI1 protein, human
• Uri1 protein, mouse
• NAD
• Diethylnitrosamine

Topics

• Animals
• Carcinoma, Hepatocellular (metabolism, pathology)
• DNA Damage
• Diethylnitrosamine
• Gene Expression Regulation, Neoplastic
• Hepatocytes (metabolism, pathology)
• Humans
• Intracellular Signaling Peptides and Proteins (genetics, metabolism)
• Liver Neoplasms (metabolism, pathology)
• Liver Neoplasms, Experimental
• Mice
• Mice, Inbred C57BL
• Molecular Sequence Data
• NAD (metabolism)
• Proteomics
• Repressor Proteins (genetics, metabolism)