Interdependence of SS18-SSX-driven YAP1 and β-catenin activation in synovial sarcoma.

Synovial sarcoma (SySa), a rare malignant soft tissue tumor, is characterized by a specific chromosomal translocation t(X;18). The resulting chimeric SS18-SSX fusion protein drives SySa pathogenesis by integrating into the BAF complex and dysregulating gene transcription. Since previous functional analyses revealed a connection between SS18-SSX and the activity of the transcriptional co-regulators YAP1/TAZ and β-catenin, respectively, this study examined a potential interdependence between these essential effector proteins in SySa. In a large cohort of SySa tissue specimens, immunohistochemical analyses revealed a substantial subset of SySa with concurrent nuclear accumulation of YAP1/TAZ and β‑catenin. In vitro, small molecule inhibitor treatment, RNAi-mediated knockdown and vector-based overexpression assays demonstrated that YAP1, TAZ and β-catenin transcriptional activity is not only stimulated by the SS18-SSX fusion protein, but that they also mutually enhance each other's activation. These analyses showed the highest cooperative effect with overexpression of YAP1 in combination with β-catenin. Co-immunoprecipitation experiments detected nuclear interactions between YAP1, β-catenin and the SS18-SSX fusion protein, the latter being an integral part of the BAF complex. Disruption of BAF complex assembly affected the coregulation of YAP1 and β-catenin, indicating that this chromatin remodeling complex plays a crucial role for interdependent YAP1 and β-catenin activation in SySa cells. Implications: This study provides deeper insights into SySa tumor biology demonstrating a mutual dependence between YAP1/TAZ and β-catenin transcriptional activity and a complex interplay with the SS18-SSX fusion protein within the BAF complex.