A super-enhancer actuated by heterodimerization of a specific YAP1 isoform, YAP1-2α, with TAZ endows cancer stemness and drug resistance

The role of alternative splicing in initiating and promoting neoplastic transformation of cells poses a significant challenge in understanding cancer. The pro-oncogenic transcriptional coactivator YAP1 comprises at least eight isoforms, but their specific and overlapping functions in cancer development remain poorly understood. Here, we show that the YAP1-2 isoform, YAP1-2 , demonstrates significantly greater activity in inducing nuclear condensates through liquid-liquid phase separation (LLPS) compared to other isoforms. Mechanistically, YAP1-2 interacts specifically with its homologue TAZ via the leucine zipper, as well as with TEADs, which are the prevalent transcriptional partners of YAP1 and TAZ. The tetrameric complex is further assembled multivalently by BRD4 to promote LLPS formation. The resulting YAP1-2 /TAZ/TEAD complex binds to super-enhancer elements and strongly enhances pro-oncogenic target gene expression in a BRD4-dependent way. Cancer cells with higher YAP1-2 levels display a clear EMT signature that drives greater malignant traits. Similarly, increased YAP1-2 levels boost pro-oncogenic features such as sphere formation, invasion of the extracellular matrix, and resistance to various stresses, including anti-cancer drugs. In high-grade serous ovarian cancers (HGSOCs), higher YAP1-2 mRNA levels are characterized by nuclear YAP1 biomolecular condensates and associated with more advanced clinical stages. Our study shows that YAP1-2 enhances cancer cell aggressiveness through LLPS formation, suggesting that the LLPS-induced YAP1-2 /TAZ/TEAD super-enhancer is a promising target for treating refractory cancers.