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

Abstract

The Hippo pathway is an important regulator of organ size and tumorigenesis. It is unclear, however, how Hippo signaling 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 tumor 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, suppresses 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.

Hopefully devoted to Q: targeting glutamine addiction in cancer

“…This supported the proliferation of human-transformed and cancer cell lines (Bott et al , 2015) as well as liver tumorigenesis in zebra fish (Cox et al , 2016). Interestingly, ectopic expression of the MYC oncogene has been shown to increase the expression of both glutaminase and GS promoting either glutamine catabolism or glutamine synthesis, respectively (Wise et al , 2008; Yuneva et al , 2012; Bott et al , 2015).…”

The receptor tyrosine kinase EphA2 promotes glutamine metabolism in tumors by activating the transcriptional coactivators YAP and TAZ

“…Although we are unable to rule out GLS2 regulation, GLS was previously identified as a transcriptional target of YAP and TAZ in pulmonary hypertension (78), suggesting this more widely expressed form of glutaminase (37) may be targeted by YAP/TAZ in multiple disease contexts. Additional YAP targets in glutamine metabolism include glutamine synthetase (GLUL) and the glutamine transporter SLC38A1 in liver cancer (79, 80), implying the EphA2-YAP/TAZ signaling axis may enhance glutamine metabolism through many gene targets. However, in the context of breast cancer, transcriptional regulation of the more catalytically-active glutaminase isoform, GAC , by TAZ supports the tumor-promoting properties associated with EphA2 and YAP/TAZ overexpression.…”

Hippo Signaling in the Liver Regulates Organ Size, Cell Fate, and Carcinogenesis

“…Interestingly, reduction of SLC38A1 (which encodes a glutamine transporter) reduces proliferation of HCC cells. Studies of this dependency on glutamine and the potential role of YAP in effecting this metabolic change (also supported by 89 ) could help identify new targets for HCC therapy.…”

“…The resultant increase in glutamine increases nucleotide biosynthesis, expanding the available nucleotide pool that fuels YAP-mediated liver growth 89 . In mice, however, liver-specific deletion of MST1 or MST2 reduces the glutamine synthase zone 74 , suggesting that upstream Hippo kinases might regulate other substrates that help to determine regulation of gene expression by YAP.…”