Jessen, M. | bioRxiv Science

bioRxiv2023

A noncanonical repressor function of JUN restrains YAP activity and suppresses YAP-dependent liver cancer growth

Yes-associated protein (YAP) and its homologue, transcriptional coactivator with PDZ-binding motif (TAZ), are the main transcriptional downstream effector of the Hippo pathway. Decreased Hippo pathway activity leads to nuclear translocation of YAP/TAZ where they interact with TEAD transcription factors to induce target gene expression. Unrestrained YAP/TAZ activity can lead to excessive growth and tumor formation in a short time, underscoring the evolutionary need for tight control of these two transcriptional coactivators. The AP-1 complex binds together with YAP/TAZ to many common sites and they form a positive feed-forward to induce gene expression. Here, we report that the AP-1 component c-JUN acts as specific repressor of YAP/TAZ at joint target sites to decrease YAP/TAZ activity. This function of c-JUN is independent of its heterodimeric AP-1 partner c-FOS demonstrating that it is independent of the canonical AP-1 function to induce target gene expression. Since c-JUN is itself by YAP/TAZ, our work identifies a negative feedback loop that buffers YAP/TAZ activity at joint sites. This negative feedback loop needs to get disrupted in liver cancer to unlock the full oncogenic potential of YAP/TAZ. Our results thus demonstrate an additional layer of control for the important interplay of YAP/TAZ and AP-1.

molecular biology↗

bioRxiv2023

Inhibition of YAP the MMB interaction and targeting NEK2 as potential therapeutic strategies for YAP-driven cancers

YAP activation in cancer is linked to poor outcomes, making it an attractive therapeutic target. Previous research focused on blocking the interaction of YAP with TEAD transcription factors. Here, we took a different approach by disrupting YAPs binding to the transcription factor B-MYB using MY-COMP, a fragment of B-MYB containing the YAP binding domain fused to a nuclear localization signal. MY-COMP induced cell cycle defects, nuclear abnormalities, and polyploidization. In an AKT and YAP-driven liver cancer model, MY-COMP significantly reduced liver tumorigenesis, highlighting the importance of the YAP-B-MYB interaction in tumor development. MY-COMP also perturbed the cell cycle progression of YAP-dependent uveal melanoma cells but not of YAP-independent cutaneous melanoma cell lines. It counteracted YAP-dependent expression of MMB-regulated cell cycle genes, explaining the observed effects. We also identified NIMA-related kinase (NEK2) as a downstream target of YAP and B-MYB, promoting YAP-driven transformation by facilitating centrosome clustering and inhibiting multipolar mitosis.

cancer biology↗