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bioRxiv · 10.1101/2025.01.28.635202

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

Ooki, T.·Hayashi, T.·Yamamoto, Y.·Hatakeyama, M.
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Abstract

The pro-oncogenic transcriptional coactivator YAP1 comprises multiple splice isoforms, including YAP1-2, which retains an intact leucine zipper by skipping exon 6. Here, we show that YAP1-2 has a markedly greater capacity to form nuclear condensates via liquid-liquid phase separation (LLPS) than other YAP1 isoforms. Mechanistically, the YAP1-2/TEAD complex interacts with the TAZ/TEAD complex through the leucine zippers on YAP1 -2 and TAZ, forming a tetrameric complex that is further assembled multivalently by BRD4 to induce LLPS. The resulting YAP1-2 /TAZ/TEAD/BRD4 complexes activate TEAD-associated super-enhancers and strongly stimulate pro-oncogenic gene expression. Cancer cells with elevated YAP1-2 display enhanced malignant traits, including sphere formation, invasion, and chemoresistance. In high-grade serous ovarian cancers (HGSOCs), higher YAP1-2 mRNA levels are associated with nuclear YAP1 biomolecular condensates and more advanced clinical stages. Our study shows that YAP1-2 drives cancer cell aggressiveness, identifying the LLPS-induced YAP1-2/TAZ/TEAD super-enhancers as a promising target for the treatment of refractory cancers.

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Ooki, T., Hayashi, T., Yamamoto, Y., Hatakeyama, M.. 2025-01-29. A super-enhancer actuated by heterodimerization of a specific YAP1 isoform, YAP1-2α, with TAZ endows cancer stemness and drug resistance. https://doi.org/10.1101/2025.01.28.635202

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