| First Author | Bisso A | Year | 2020 |
| Journal | Hepatology | Volume | 72 |
| Issue | 4 | Pages | 1430-1443 |
| PubMed ID | 31965581 | Mgi Jnum | J:339432 |
| Mgi Id | MGI:7522557 | Doi | 10.1002/hep.31120 |
| Citation | Bisso A, et al. (2020) Cooperation Between MYC and beta-Catenin in Liver Tumorigenesis Requires Yap/Taz. Hepatology 72(4):1430-1443 |
| abstractText | BACKGROUND AND AIMS: Activation of MYC and 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 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/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-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. |
