A non-canonical repressor function of JUN restrains YAP activity and liver cancer growth.

Yes-associated protein (YAP) and its homolog, transcriptional coactivator with PDZ-binding motif (TAZ), are the main transcriptional downstream effectors 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. Here, we report that the AP-1 component JUN acts as specific repressor of YAP/TAZ at joint target sites to decrease YAP/TAZ activity. This function of JUN is independent of its heterodimeric AP-1 partner FOS and the canonical AP-1 function. Since expression of JUN is itself induced by YAP/TAZ, our work identifies a JUN-dependent negative feedback loop that buffers YAP/TAZ activity at joint genomic sites. This negative feedback loop gets disrupted in liver cancer to unlock the full oncogenic potential of YAP/TAZ. Our results thus demonstrate an additional layer of control for the interplay of YAP/TAZ and AP-1. Synopsis: AP-1 transcription factor complexes formed by JUN/FOS are required for full transcriptional activity of YAP/TAZ in cancer. This work identifies an unexpected FOS-independent role of JUN in buffering oncogenic YAP/TAZ activity at target genes, providing a negative feedback mechanism in liver cancer. JUN antagonizes YAP activation-induced growth arrest in human cancer cells by interfering with YAP target gene expression. JUN acts as specific repressor of YAP/TAZ transcriptional activity at joint target sites. JUN-mediated YAP/TAZ repression depends on JUN homodimerization and corepressor proteins NCOR1/2, but is independent of its heterodimeric AP-1 partner FOS. Overexpression of FOS-binding incompetent JUN suppresses YAP-dependent liver cancers. Negative feedback signaling by homodimerized JUN-JUN-NCOR1/2 repressor complex acts as a tumor suppressor by buffering oncogenic YAP/TAZ activity in hepatocellular carcinoma. [ABSTRACT FROM AUTHOR]