Upregulated YAP promotes oncogenic CTNNB1 expression contributing to molecular pathology of hepatoblastoma.

Background: Hepatoblastoma (HB) is one of the most common cancers in children. Recent studies have shown that the occurrence of nuclear accumulation of β-catenin reaches 90%-100% because of the anomalous activation of the Wnt pathway in HB patients. Furthermore, emerging studies have shown that concomitant activated forms of YAP and β-catenin trigger the formation and progression of HB. YAP might play a vital role in β-catenin-mediated HB development. However, the molecular mechanisms by which YAP/TEAD4 transcription factor regulates CTNNB1 underlying HB pathogenesis are still unclear.

Procedure: YAP and CTNNB1 expression and correlation were analyzed by a combination of network enrichment analysis and gene set enrichment analysis of the public microarray datasets (GSE131329 and GSE81928). The protein levels of YAP and β-catenin were further validated by Western blotting in paired patients' samples. The direct interplay between YAP/TEAD4 and the promoter region of CTNNB1 was proven by the combination of dual-luciferase report assay and chromatin immunoprecipitation assay.

Results: YAP-conserved signature and WNT signaling pathway were significantly enriched in HB patients, with upregulated expression of YAP and β-catenin compared to non-HB patients. Further functional assays demonstrated that YAP/TEAD4 transcription factor complex could bind to the CTNNB1 promoter region directly to promote β-catenin expression and cell proliferation. Targeting the YAP/TEAD4 complex with a specific small-molecule compound markedly suppressed HepaG2 cell proliferation.

Conclusions: As the upstream transcription factor of CTNNB1, YAP/TEAD4 is a promising target for the treatment of HB patients with high levels of YAP and β-catenin.