Invited Speaker Oral 2nd Australian Cancer and Metabolism Meeting 2017

The Hippo pathway’s sweet tooth: Yap reprograms glucose metabolism to fuel tissue growth. (#12)

Andrew Cox 1
  1. University of Melbourne, Melbourne, VIC, Australia

The Hippo pathway and its nuclear effector Yap play a central role in the regulation of organ size control and cancer. While many inputs regulating the Hippo pathway have been identified, less is known about the Yap target genes responsible for the remarkable effects on tissue growth. Here, we show that yap-/- mutant zebrafish exhibit defects in hepatic progenitor potential and liver growth that persist into adulthood. Transcriptional profiling reveals that Yap directly regulates expression of glucose transporters glut1 and glut2. Metabolic analysis reveals yap-/- mutant zebrafish to be glucose intolerant with decreased glycolytic flux into anabolic nucleotide biosynthesis. Importantly, we show that glucose transport is conditionally required for Yap-driven liver growth. Furthermore, we demonstrate that glut1 is regulated directly by Yap via an intragenic enhancer element that is conserved in mammals. Finally, we use a transgenic liver-specific TetONYap mouse model to demonstrate that Yap stimulates glucose uptake prior to the onset of malignancy. Thus, our results identify glut1 as a direct target of Yap that enhances glucose uptake and utilization for the anabolic biosynthesis of nucleotides required for organ growth.