The Hippo effector TAZ cooperates with oncogenic β-catenin in experimental and human hepatoblastoma development

Abstract Backgrounds: Hepatoblastoma (HB) is the most common pediatric liver tumor. Though Wnt/β-catenin and Hippo cascades are implicated in HB development, there is no study on the crosstalk of β-catenin and Hippo downstream effector TAZ in HB. Methods: The expression of TAZ and of β-catenin in human HB specimens was assessed by immunohistochemistry (IHC). The functional interplay between TAZ and β-catenin was tested through delivering either an activated form of TAZ (TAZS89A) alone or co-delivering TAZS89A and an activated form of β-catenin (∆N90-β-catenin) to mouse liver using sleeping beauty transposase via hydrodynamic tail vein injection (SBT-HTVI). In addition, the role of transcriptional enhanced associate domain (TEAD) factors, canonical Notch cascade, Yap, and the tumor modifier heat shock transcription factor 1 (HSF1) along TAZ/β-catenin-driven HB development was studied in vivo and vitro. Results: Activation of TAZ often co-occurred with that of β-catenin in clinical specimens. While overexpression of TAZS89A alone was unable to promote liver tumorigenesis, the concomitant overexpression of TAZ and ∆N90-β-catenin induced the development of HB lesions exhibiting both epithelial and mesenchymal features. Mechanistically, HB development driven by TAZ/β-catenin required TAZ interaction with TEAD factors. Furthermore, TAZ/β-catenin overexpression induced HB development in conditional Yes-associated protein knockout (Yap KO) mice, indicating that Yap activation is dispensable in this model. Activation of the Notch signaling was observed in TAZ/β-catenin mouse lesions, consistent with that reported in human HBs. Blocking of the canonical Notch cascade using the dominant negative form of RBP-J (dnRBP-J) did not inhibit TAZ/β-catenin dependent HB formation in mice, although suppressed the mesenchymal differentiation. Similarly, upregulation of HSF1 was detected in TAZ/β-catenin lesions, but its inactivation did not affect HB development. 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 β-catenin or YAP gene. Conclusions: Overall, our study identifies TAZ as a critical oncogene in HB development and progression. Yap, Notch, and HSF1 are dispensable for TAZ/β-catenin induced HB development in mice.