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

Cancer cells with homologous recombination defects are particularly susceptible to PARP inhibitors (PARPi) and experience synthetic lethality. We found that the development of PARPi resistance in these cancer cells is associated with the formation of nuclear membrane-less condensates containing a specific YAP1 variant termed YAP1-2α, TAZ, TEAD, and BRD4. These nuclear condensates are generated through liquid-liquid phase separation (LLPS), initiated by the heterodimerization of YAP1-2α with TAZ, followed by multivalent interactions with mediator proteins to activate a super-enhancer. This super-enhancer facilitates the robustness of cancer cells by increasing cancer stemness, contributing to anti-cancer drug resistance not limited to PARPi. Our study underscores the unexpected connection between RNA splicing and the malignant grade of cancer. Targeting YAP1-2α/TAZ/TEAD-driven super-enhancers is a promising approach for overcoming resistance to cancer treatment. RNA-seq profiling of parental cells (UWB1.289 and MDA-MB-436) and their PARPi-resistant cells. RNA-seq profiling of control MDA-MB-436 cells, YAP1-2g-expressing MDA-MB-436 cells, YAP1-2a-expressing MDA-MB-436 cells and BRD4-depleted YAP1-2a-expressing MDA-MB-436 cells.