TY - JOUR
T1 - Cooperation Between MYC and β-Catenin in Liver Tumorigenesis Requires Yap/Taz
AU - Bisso, Andrea
AU - Filipuzzi, Marco
AU - Gamarra Figueroa, Gianni Paolo
AU - Brumana, Giulia
AU - Biagioni, Francesca
AU - Doni, Mirko
AU - Ceccotti, Giorgia
AU - Tanaskovic, Nina
AU - Morelli, Marco Jacopo
AU - Pendino, Vera
AU - Chiacchiera, Fulvio
AU - Pasini, Diego
AU - Olivero, Daniela
AU - Campaner, Stefano
AU - Sabò, Arianna
AU - Amati, Bruno
N1 - Funding Information:
We thank Gioacchino Natoli, Ottavio Croci, Thomas Valenta, Konrad Basler, and members of the Amati?s and Campaner?s labs for discussion and advice. We also thank Konrad Basler, Eduard Battle, Pierre Chambon, Stefano Piccolo, Makoto Taketo, and Thomas Valenta for materials, Camilla Recordati for initial pathological analyses, A. Gobbi, M. Capillo, and all the members of the animal facility for their help with the management of mouse colonies, and S. Bianchi, L. Rotta, and T. Capra for assistance with Illumina sequencing.
Publisher Copyright:
© 2020 by the American Association for the Study of Liver Diseases.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/10/1
Y1 - 2020/10/1
N2 - 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.
AB - 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.
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U2 - 10.1002/hep.31120
DO - 10.1002/hep.31120
M3 - Article
C2 - 31965581
AN - SCOPUS:85088710410
VL - 72
SP - 1430
EP - 1443
JO - Hepatology
JF - Hepatology
SN - 0270-9139
IS - 4
ER -