Abstract 5638: The BAF complex mediates intertwined activity of YAP1 and β-catenin in synovial sarcoma

Abstract

Abstract Introduction: Synovial sarcoma (SySa) is a rare malignant soft tissue tumor characterized by a specific reciprocal translocation t(X;18). The resulting chimeric SS18::SSX fusion protein drives SySa tumorigenesis by integrating into BAF chromatin remodeling complexes, changing their composition and dysregulating gene transcription. The role of BAF complexes in cancer steadily increases with ∼20% of all malignancies having alterations in BAF complex subunits. BAF complexes are multiprotein complexes with several interaction partners determining their localization and functionality. Since previous analyses revealed an induced activation of the transcriptional coregulators YAP1 and β-catenin in SySa, the aim of this study was to analyze if nuclear YAP1 and β-catenin are interacting with BAF complexes and if this has an impact on their transcriptional activity. Experimental procedures: Co-immunoprecipitation experiments on nuclear protein extracts and proximity ligation assays were performed to investigate interactions between YAP1, β-catenin, and BAF complex subunits in SySa cells. Knockdown of common and specific BAF complex subunits was conducted employing RNA interference. To assess changes in YAP1 and β-catenin transcriptional activities, TEAD and TOPFlash luciferase reporter assays were performed, respectively, and protein expression levels were detected by immunoblotting. Results: In SySa, protein-protein interaction experiments revealed nuclear interactions between β-catenin, YAP1, the SS18::SSX fusion protein and various BAF subunits. YAP1 and β-catenin’s transcriptional activities were found to be interdependent as they mutually enhanced each other’s activation. Knockdown of SS18::SSX as well as specific BAF complex subunits was associated with diminished transcriptional activities of these coregulators and, interestingly, substantially affected their mutual activation. This indicates that SS18::SSX-containing BAF complex assembly is crucial for interdependent YAP1 and β-catenin activation in SySa cells. Conclusions: This study reveals a significant role of the SySa-specific fusion protein and BAF chromatin remodeling complexes in mediating intertwined activation of YAP1 and β-catenin. Citation Format: Ilka Isfort, Ruth Berthold, Lorena Heinst, Anna Kuntze, Eva Wardelmann, Marcel Trautmann, Wolfgang Hartmann. The BAF complex mediates intertwined activity of YAP1 and β-catenin in synovial sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5638.