The Hippo pathway effector YAP inhibits NF-κB signaling and ccRCC growth by opposing ZHX2.

The prevailing view in the cancer field is that Hippo (Hpo) signaling pathway functions as a tumor suppressor pathway by blocking the oncogenic potential of the pathway effectors Yes1-associated transcriptional regulator (YAP)/transcriptional coactivator with PDZ-binding motif. However, YAP can also function as a context-dependent tumor suppressor in several types of cancer including clear cell renal cell carcinomas (ccRCCs). We find that, in addition to inhibiting hypoxia-inducible factor 2α, a major oncogenic driver in Von Hippel-Lindau-/- ccRCC, YAP also blocks nuclear factor κB (NF-κB) signaling in ccRCC to inhibit cancer cell growth under conditions where hypoxia-inducible factor 2α is dispensable. Mechanistically, YAP inhibits the expression of Zinc fingers and homeoboxes 2 (ZHX2), a Von Hippel-Lindau substrate and critical cofactor of NF-κB in ccRCC. Furthermore, YAP competes with ZHX2 for binding to the NF-κB subunit p65. Consequently, elevated nuclear YAP blocks the cooperativity between ZHX2 and the NF-κB subunit p65, leading to diminished NF-κB target gene expression. Pharmacological inhibition of Hpo kinase blocked NF-κB transcriptional program and suppressed ccRCC cell growth, which can be rescued by overexpression of ZHX2 or p65. Our study uncovers a crosstalk between the Hpo and NF-κB/ZHX2 pathways and its involvement in ccRCC growth inhibition, suggesting that targeting the Hpo pathway may provide a therapeutical opportunity for ccRCC treatment.