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DOI: 10.1055/s-0030-1269527
Epigenetic and post-transcriptional mechanisms are responsible for disruption of the Hippo tumor suppressor pathway in human hepatocellular carcinoma
Mounting evidence indicates that disruption of the Hippo tumor suppressor pathway contributes to hepatocarcinogenesis. In this study, we investigated the expression levels of the members of the Hippo signaling in a collection of human hepatocellular carcinoma (HCC) as well as in in vivo and in vitro models. Thus, promoter and genomic status of Hippo pathway members were assessed in HCC by methylation and microsatellite analyses, while effects of Hippo modulation on HCC growth were evaluated in HCC cell lines. We found that suppression of FAT4, NF2, MST1, MST2, LATS1, LATS2 and SAV1 expression by promoter hypermethylation and/or loss of heterozygosity was rare in HCC. However, levels of activated YAP, the protooncogene negatively modulated by the Hippo cascade, were high in most HCC when compared with corresponding non-tumorous surrounding livers, implying the existence of post-transcriptional mechanisms responsible for suppression of the Hippo pathway in human HCC. Indeed, we found that MST1 and MST2 were inactivated via phosphorylation at serine 120 and 117 residues, respectively, by the AKT. In HCC cell lines, transfection of AKT led to increased proliferation and decreased apoptosis that were paralleled by phosphorylation of MST1 and MST2 and activation of YAP protooncogene. AKT-driven growth of HCC cell lines was significantly decreased when AKT transfection was associated with silencing of YAP via siRNA. Accordingly, a strong suppression of MST1 and MST2 activity, with resulting activation of YAP, followed the stable transfection of an activated form of AKT into the mouse liver by hydrodynamic gene delivery. In conclusion, we have defined the epigenetic and post-transcriptional mechanisms responsible for suppression of Hippo signaling pathway in liver cancer. Also, our data imply AKT as the major negative regulator of Hippo cascade in human HCC and support the use of AKT inhibitors as therapeutic modality for human HCC.
AKT - HCC - Hepatocarcinogenesis - Hippo pathway - MST1 - MST2 - YAP