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Yap reprograms glutamine metabolism to increase nucleotide biosynthesis and enable liver growth

2016; Nature Portfolio; Volume: 18; Issue: 8 Linguagem: Inglês

10.1038/ncb3389

1476-4679

Andrew G. Cox, Katie L. Hwang, Kristin Brown, Kimberley Evason, Sebastian Beltz, Allison Tsomides, Keelin O’Connor, Giorgio Giacomo Galli, Dean Yimlamai, Sagar Chhangawala, Min Yuan, Evan C. Lien, Julia Wücherpfennig, Sahar Nissim, Akihiro Minami, David E. Cohen, Fernando D. Camargo, John M. Asara, Yariv Houvras, Didier Y. R. Stainier, Wolfram Goessling,

RNA Research and Splicing

The Hippo pathway is an important regulator of organ size and tumorigenesis. It is unclear, however, how Hippo signalling provides the cellular building blocks required for rapid growth. Here, we demonstrate that transgenic zebrafish expressing an activated form of the Hippo pathway effector Yap1 (also known as YAP) develop enlarged livers and are prone to liver tumour formation. Transcriptomic and metabolomic profiling identify that Yap1 reprograms glutamine metabolism. Yap1 directly enhances glutamine synthetase (glul) expression and activity, elevating steady-state levels of glutamine and enhancing the relative isotopic enrichment of nitrogen during de novo purine and pyrimidine biosynthesis. Genetic or pharmacological inhibition of GLUL diminishes the isotopic enrichment of nitrogen into nucleotides, suppressing hepatomegaly and the growth of liver cancer cells. Consequently, Yap-driven liver growth is susceptible to nucleotide inhibition. Together, our findings demonstrate that Yap1 integrates the anabolic demands of tissue growth during development and tumorigenesis by reprogramming nitrogen metabolism to stimulate nucleotide biosynthesis. Cox et al. report that Yap induces the expression of glutamine synthetase, thereby elevating glutamine and nitrogen levels for de novo nucleotide synthesis. They show that this promotes hepatomegaly and growth of liver cancer cells in zebrafish.