The Hippo Effector Transcriptional Coactivator with PDZ-Binding Motif Cooperates with Oncogenic β-Catenin to Induce Hepatoblastoma Development in Mice and Humans

Abstract

Hepatoblastoma (HB) is the most common pediatric liver tumor. Though Wnt/β-catenin and Hippo cascades are implicated in HB development, studies on crosstalk between β-catenin and Hippo downstream effector transcriptional coactivator with PDZ-binding motif (TAZ) in HB are lacking. Expression levels of TAZ and β-catenin in human HB specimens were assessed by immunohistochemistry. Functional interplay between TAZ and β-catenin was determined by overexpression of an activated form of TAZ (TAZS89A), either alone or combined with an oncogenic form of β-catenin (ΔN90-β-catenin), in mouse liver via hydrodynamic transfection. Activation of TAZ often co-occurred with that of β-catenin in clinical specimens. Although the overexpression of TAZS89A alone did not induce hepatocarcinogenesis, concomitant overexpression of TAZS89A and ΔN90-β-catenin triggered the development of HB lesions exhibiting both epithelial and mesenchymal features. Mechanistically, TAZ/β-catenin-driven HB development required TAZ interaction with transcriptional enhanced associate domain factors. Blockade of the Notch cascade did not inhibit TAZ/β-catenin-dependent HB formation in mice but suppressed the mesenchymal phenotype. Neither Yes-associated protein nor heat shock factor 1 depletion affected HB development in TAZ/β-catenin mice. In human HB cell lines, silencing of TAZ resulted in decreased cell growth, which was further reduced when TAZ knockdown was associated with suppression of either β-catenin or Yes-associated protein. Overall, our study identified TAZ as a crucial oncogene in HB development and progression.