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

ABSTRACT The acquisition of drug resistance poses a significant challenge for successful cancer treatment. Understanding the mechanisms by which cancer evades drug action is crucial for developing effective therapies. PARP inhibitors (PARPi) induce synthetic lethality in BRCA -deficient cancer cells; however, these cells eventually develop PARPi resistance. Here, we demonstrate that prolonged exposure of BRCA -deficient cancer cells to PARPi or Cisplatin leads to alterations in YAP1 pre-mRNA splicing patterns, resulting in selective upregulation of a minor YAP1 isoform, YAP1-2α. Elevated YAP1-2α specifically heterodimerizes with TAZ, triggering liquid-liquid phase separation (LLPS). This process generates nuclear condensates that activate super-enhancers containing the YAP1-2α/TAZ heterodimer, TEAD, and BRD4. These super-enhancers (here referred to as YAP1-2α/TAZ/TEAD super-enhancers) are also activated in CD44(variant) high cancer stem-like populations in parental cells. In both PARPi-resistant and CD44(variant) high cancer cell populations, treatments that disrupt YAP1-2α/TAZ/TEAD super-enhancers abolish cancer stem-like properties. Thus, the activation of YAP1-2α/TAZ/TEAD super-enhancers reinforces cancer cell stemness, which confers resistance to adverse conditions, such as those caused by anticancer drug treatment, including PARPi and Cisplatin. Our investigation reveals that YAP1-2α/TAZ/TEAD super-enhancers transcriptionally facilitate the malignant grade of cancer cells. Disrupting these super-enhancers represents a promising strategy to hinder neoplastic progression and prevent multidrug resistance in cancer cells.