The Hippo effector TAZ cooperates with oncogenic beta-catenin to induce hepatoblastoma development in mice and humans.

Hepatoblastoma (HB) is the most common pediatric liver tumor. Though Wnt/beta-catenin and Hippo cascades are implicated in HB development, studies on the crosstalk between beta-catenin and Hippo downstream effector TAZ in HB are lacking. Expression of TAZ and beta-catenin in human HB specimens was assessed by immunohistochemistry (IHC). Functional interplay between TAZ and beta-catenin was determined by overexpressing an activated form of TAZ (TAZS89A) either alone or in combination with an oncogenic form of beta-catenin (DeltaN90-beta-catenin) in the mouse liver via hydrodynamic transfection. We found that activation of TAZ often co-occurred with that of beta-catenin in clinical specimens. While overexpression of TAZS89A alone was unable to induce hepatocarcinogenesis, concomitant overexpression of TAZS89A and DeltaN90-beta-catenin triggered the development of HB lesions exhibiting both epithelial and mesenchymal features. Mechanistically, TAZ/beta-catenin-driven HB development required TAZ interaction with transcriptional enhanced associate domain (TEAD) factors. Blockade of the Notch cascade did not inhibit TAZ/beta-catenin dependent HB formation in mice but suppressed the mesenchymal phenotype. Furthermore, neither Yes-associated protein (YAP) nor Heat-shock factor 1 (HSF1) depletion affected HB development in TAZ/beta-catenin mice. In human HB cell lines, silencing of TAZ resulted in decreased cell growth, which was reduced more substantially when TAZ knockdown was associated with suppression of either beta-catenin or YAP. Overall, our study identifies TAZ as a critical oncogene in HB development and progression.