Cooperation between MYC and β‐catenin in liver tumorigenesis requires Yap/Taz

BACKGROUND & AIMS: Activation of MYC and CTNNB1 (encoding beta-catenin) can co-occur in liver cancer, but how these oncogenes cooperate in tumorigenesis remains unclear. Approach & Results We generated a mouse model allowing conditional activation of MYC and WNT/beta-catenin signaling (through either beta-catenin activation or Apc loss) upon expression of CRE recombinase in the liver, and monitored their effects on hepatocyte proliferation, apoptosis, gene expression profiles and tumorigenesis. Activation of WNT/beta-catenin signaling strongly accelerated MYC-driven carcinogenesis in the liver. Both pathways also cooperated in promoting cellular transformation in vitro, demonstrating their cell-autonomous action. Short-term induction of MYC and beta-catenin in hepatocytes followed by RNA-seq profiling allowed the identification of a "Myc/beta-catenin signature", composed of a discrete set of Myc-activated genes whose expression increased in the presence of active beta-catenin. Notably this signature enriched for targets of Yap and Taz, two transcriptional co-activators known to be activated by WNT/beta-catenin signaling, and to cooperate with MYC in mitogenic activation and liver transformation. Consistent with these regulatory connections, Yap/Taz accumulated upon Myc/beta-catenin activation and were required not only for the ensuing proliferative response, but also for tumor cell growth and survival. Finally, the Myc/beta-catenin signature was enriched in a subset of human hepatocellular carcinomas characterized by comparatively poor prognosis. CONCLUSIONS: Myc and beta-catenin show a strong cooperative action in liver carcinogenesis, with Yap and Taz serving as mediators of this effect. These findings warrant efforts toward therapeutic targeting of Yap/Taz in aggressive liver tumors marked by elevated Myc/beta-catenin activity.