Cooperation Between MYC and β-Catenin in Liver Tumorigenesis Requires Yap/Taz

Background and Aims Activation ofMYCand catenin beta-1 (CTNNB1, encoding beta-catenin) can co-occur in liver cancer, but how these oncogenes cooperate in tumorigenesis remains unclear. Approach and Results We generated a mouse model allowing conditional activation of MYC and WNT/beta-catenin signaling (through either beta-catenin activation or loss ofAPC- adenomatous polyposis coli) 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 transformationin vitro, demonstrating their cell-autonomous action. Short-term induction of MYC and beta-catenin in hepatocytes, followed by RNA-sequencing 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 Yes-associated protein (Yap) and transcriptional coactivator with PDZ-binding motif (Taz), two transcriptional coactivators 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.