Poster Presentation 29th Lorne Cancer Conference 2017

Yap regulates anabolic glucose metabolism to fuel premalignant growth (#146)

Andrew G Cox 1 2 3 , Wolfram Goessling 3 4 5 6 7
  1. Peter MacCallum Cancer Centre, The University of Melbourne, Melbourne, Victoria, Australia
  2. Department of Biochemistry and Molecular Biology, The Univeristy of Melbourne, Melbourne, Victoria, Australia
  3. Genetics Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
  4. Harvard-MIT Division of Health Sciences and Technology, Boston, MA, USA
  5. Gastrointestinal Cancer Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
  6. Broad Institute of MIT and Harvard, Boston, MA, USA
  7. Harvard Stem Cell Institute, Boston, MA, USA

The Hippo pathway plays a central role in the regulation of organ size, stem cell homeostasis and cancer. Although many of the inputs into the Hippo pathway have been identified, less is known about how Yap target genes mediate the remarkable effects on tissue growth. Here, we show that yap-/- mutant zebrafish have defects in liver growth and hepatic progenitor potential that persist into adulthood. Transcriptional profiling reveals that Yap is necessary and sufficient to regulate expression of the glucose transporters, glut1 and glut2. Metabolic analysis identifies that yap-/- mutant zebrafish are glucose intolerant and exhibit decreased glycolytic flux into the anabolic biosynthesis of nucleotides. Further, normal glucose transport and nucleotide biosynthesis are conditionally required for Yap-driven liver growth. Finally, we demonstrate that the regulation of glut1 expression and glucose uptake is conserved in mammals. Taken together, our findings reveal that Yap directly induces glut1 to enhance glucose uptake and fuel the anabolic biosynthesis of nucleotides required to stimulate liver growth.