Interdependence of SS18-SSX-driven YAP1 and b-Catenin Activation in Synovial Sarcoma

Synovial sarcoma, a rare malignant soft tissue tumor, is charac-terized by a specific chromosomal translocation t(X;18). The result-ing chimeric SS18-SSX fusion protein drives synovial sarcoma pathogenesis by integrating into the BAF complex and dysregulating gene transcription. Because previous functional analyses revealed a connection between SS18-SSX and the activity of the transcriptional coregulators YAP1/TAZ and 13-catenin, respectively, this study examined a potential interdependence between these essential effec-tor proteins in synovial sarcoma. In a large cohort of synovial sarcoma tissue specimens, IHC analyses revealed a substantial subset of synovial sarcoma with concurrent nuclear accumulation of YAP1/TAZ and 13-catenin. In vitro , small-molecule inhibitor treatment, RNAi-mediated knockdown, and vector-based overex-pression assays demonstrated that YAP1, TAZ, and 13-catenin tran-scriptional 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 overex-pression of YAP1 in combination with 13-catenin. Coimmunopreci-pitation experiments detected nuclear interactions between YAP1, 13-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 13-catenin, indicating that this chromatin remodeling complex plays a crucial role for interdependent YAP1 and 13-catenin activation in synovial sarcoma cells.Implications: This study provides deeper insights into synovial sarcoma tumor biology demonstrating a mutual dependence between YAP1/TAZ and 13-catenin transcriptional activity and a complex interplay with the SS18-SSX fusion protein within the BAF complex.