Inhibition of De Novo NAD+ Synthesis by Oncogenic URI Causes Liver Tumorigenesis through DNA Damage

Written by
Krishna S. Tummala
Published on
August 30, 2021 10:56:00 AM PDT August 30, 2021 10:56:00 AM PDTth, August 30, 2021 10:56:00 AM PDT

Authors: Krishna S. Tummala, Ana L. Gomes, Mahmut Yilmaz, Osvaldo Grana, Latifa Bakiri, Isabel Ruppen, Pilar Ximenez-Embun, Vinayata Sheshappanavar, Manuel Rodriguez-Justo, David G. Pisano, Erwin F. Wagner, and Nabil Djouder


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.


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