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

Hepatology. 2020 Oct;72(4):1430-1443. doi: 10.1002/hep.31120. Epub 2020 Jul 29.


Background and aims: Activation of MYC and catenin beta-1 (CTNNB1, encoding β-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/β-catenin signaling (through either β-catenin activation or loss of APC - 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/β-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 β-catenin in hepatocytes, followed by RNA-sequencing profiling, allowed the identification of a "Myc/β-catenin signature," composed of a discrete set of Myc-activated genes whose expression increased in the presence of active β-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/β-catenin signaling and to cooperate with MYC in mitogenic activation and liver transformation. Consistent with these regulatory connections, Yap/Taz accumulated upon Myc/β-catenin activation and were required not only for the ensuing proliferative response, but also for tumor cell growth and survival. Finally, the Myc/β-catenin signature was enriched in a subset of human hepatocellular carcinomas characterized by comparatively poor prognosis.

Conclusions: Myc and β-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/β-catenin activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / physiology*
  • Animals
  • Cell Cycle Proteins / physiology*
  • Liver Neoplasms, Experimental / etiology*
  • Mice
  • Mice, Inbred C57BL
  • Proto-Oncogene Proteins c-myc / physiology*
  • Trans-Activators / physiology*
  • Wnt Signaling Pathway / physiology
  • YAP-Signaling Proteins
  • beta Catenin / physiology*


  • Adaptor Proteins, Signal Transducing
  • CTNNB1 protein, mouse
  • Cell Cycle Proteins
  • Myc protein, mouse
  • Proto-Oncogene Proteins c-myc
  • Trans-Activators
  • Wwtr1 protein, mouse
  • YAP-Signaling Proteins
  • Yap1 protein, mouse
  • beta Catenin