Abstract 5151: Yap reprograms glutamine metabolism and supports growth during liver development and tumorigenesis

Abstract

Hepatocellular carcinoma is a global health problem with poor prognosis and limited therapeutic options. Recently, the Hippo pathway has emerged as a master regulator of organ size control and tumorigenesis. However, the metabolic impact of the pathway is poorly understood. Using a transgenic zebrafish model with liver-specific activation of the Hippo pathway effector Yap, we have shown that Yap promotes hepatomegaly and liver dysplasia. In addition, we demonstrate that the Yap transgenics are highly susceptible to chemically-induced hepatocarcinogenesis. Transcriptomic and metabolomic profiling reveals that Yap enhances glutamine synthase (GS) expression and elevates steady-state levels of glutamine, respectively. Intervention studies with the GS inhibitor methionine sulfoximine established that elevated GS activity contributes to the rapid liver growth observed during Yap-driven hepatomegaly. Finally, studies in cultured human cancer cells identify GS as a bone-fide Yap target gene, confirming that the GS regulation by Yap is evolutionarily conserved. We conclude that Yap regulates GS expression and reprograms nitrogen metabolism, which contributes to liver growth during development and tumorigenesis. We hypothesize that Yap integrates the anabolic demands of rapid cell proliferation by increasing the flux of glutamine into nucleotide biosynthesis. Citation Format: Andrew G. Cox, Katie L. Hwang, Kimberley Evason, Kristin K. Brown, Sebastian Beltz, Keelin O'Connor, Giorgio G. Galli, Dean Yimlamai, Sagar Chhangawala, Evan Lien, Fernando D. Camargo, John Asara, Yariv Houvras, Didier Y. Stainier, Wolfram Goessling. Yap reprograms glutamine metabolism and supports growth during liver development and tumorigenesis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5151. doi:10.1158/1538-7445.AM2015-5151