YAP1-2α-TAZ heterodimerization promotes BRD4-associated LLPS-like assembly at candidate super-enhancers and cancer cell malignancy

YAP1 is a transcriptional coactivator expressed as multiple splice isoforms, but how individual isoforms specify malignant cell states remains unclear. Here, we identify YAP1-2 as an isoform that drives a distinct transcriptional state in cancer cells. The YAP1-2-TAZ heterodimer, together with TEAD, forms BRD4-associated nuclear assemblies with LLPS-like properties. These assemblies are enriched at candidate super-enhancer-associated regions and promote transcription. Disrupting YAP1-2-TAZ heterodimerization, TEAD binding, or BRD4 interaction impairs assembly formation and associated phenotypes. Exon-6 exclusion promotes YAP1-2-associated nuclear puncta, invasion, and therapeutic resistance in high-grade serous ovarian cancer (HGSOC), and enhances intraperitoneal tumor progression in gastric cancer xenografts. Gastric cancer cells selected through peritoneal dissemination exhibit increased YAP1-2, nuclear YAP1 puncta, and therapeutic resistance. In HGSOC specimens, YAP1-2 abundance, YAP1-BRD4 proximity, and nuclear YAP1 puncta are associated with advanced stages. Thus, YAP1-2 drives a BRD4-associated condensate-like transcriptional state linked to malignant progression across multiple cancer contexts.