β-Catenin regulates distinct pathways from YAP and suppresses ONECUT1 to drive hepatoblastoma development in mice and humans.

BACKGROUND AND AIMS

Hepatoblastoma (HB) is the predominant primary malignant liver tumor in childhood. Concomitant Yes-associated protein (YAP) and β-Catenin activation occurs in most HB. However, the signaling pathways distinctively regulated by YAP and β-Catenin protooncogenes in HB remain unexplored.

APPROACH AND RESULTS

We engineered an inducible HB murine model using hydrodynamic injection to deliver transposon plasmids encoding constitutive YAP and doxycycline (Dox)-inducible ΔN90-β-Catenin(YAP/TRE-β-Catenin). Gene expression patterns in mouse HB lesions were analyzed upon short-term Dox withdrawal, that is, tumors still existed but ΔN90-β-Catenin was turned off. The mice rapidly developed aggressive HB lesions when fed Dox. However, upon Dox withdrawal, HB regressed, although tumors did not completely disappear over a long time. At the molecular level, YAP and β-Catenin were found to regulate distinct gene expression programs in HB. Specifically, YAP controls the Hippo and metabolism-related pathways, whereas β-Catenin modulates immune-related pathways, contributing to immune exclusion in the tumor microenvironment. Furthermore, we identified the transcription factor ONECUT1 as a tumor suppressor gene downregulated by activated β-Catenin in HB. Low ONECUT1 expression also characterizes human HB, and the co-expression of ONECUT1 strongly suppressed YAP/β-Catenin-driven HB formation in the mice. Mechanistically, ONECUT1 functions downstream of activated β-Catenin and negatively regulates tumor cell glycolysis.

CONCLUSIONS

We show that suppressing activated β-Catenin could hamper HB progression in vivo by affecting pathways distinct from those regulated by YAP in HB. The inhibition of ONECUT1 expression by β-Catenin might represent a critical molecular event leading to HB formation.