The desmosomal cadherin desmoglein-2 regulates the Hippo pathway effector yes-associated protein (YAP) in liver cancer

Parenchymal hepatocytes are highly organized in a 3-dimensional network while loss of cell-cell contacts and cellular polarity are key feature in chronic liver damage and hepatocarcinogenesis. In this context, cadherins are key factors in the formation of junctional structures and maintain cell polarity in hepatocytes. Previous data illustrate that the Hippo pathway is a regulator of cell autonomous organ growth due to its ability to sense extracellular information, thereby negatively regulating the oncogene yes-associated protein (YAP). However, if and to which extent reorganization of junctional structures impair hepatocellular functionality in a Hippo pathway-dependent manner is not well understood. In this project we aim to understand how junctional proteins may affect liver cancer development via the Hippo/YAP axis.

To identify junctional factors with potential impact on the Hippo/YAP pathway, expression data from primary human hepatocellular cancer (HCC) tissues and respective surrounding liver tissues were analyzed (n = 247; Roessler et al., 2010). Several junctional proteins were significantly dysregulated in HCC tissues (e.g. Cadherin-2, Desmoglein-3). Similarly, the desmosomal cadherin desmoglein-2 (DSG2) was overexpressed in HCCs (p < 0.001) and its expression correlated with shorter patient survival (p = 0.066). Importantly, DSG2 expression significantly associated with the expression of a YAP-dependent gene signature (r = 0.448, p < 0.001). Indeed, Western blotting and immunofluorescence analyses revealed that siRNA-mediated DSG2 reduction led to a nuclear export of YAP in HCC cell lines. In addition, the concentration of typical YAP target genes was diminished at the transcript and protein levels (e.g. cysteine rich angiogenic inducer 61, CYR61). Functionally, DSG2 inhibition phenocopies reduced HCC cell viability.

These data suggest that the reorganisation of desmosomal structures affects YAP activity and may represent a novel upstream regulator of the Hippo pathway in liver tumorigenesis.