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

Abstract 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.