YAP inhibits NF-κB signaling and ccRCC growth by opposing p65-ZHX2 cooperativity

Abstract

The prevailing view in the cancer field is that Hippo 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 (TAZ). However, YAP can also function as a context-dependent tumor suppressor in several types of cancer including clear cell renal cell carcinomas (ccRCC). We find that, in additional to inhibiting hypoxia-inducible factor 2 (HIF2), a major oncogenic driver in Von Hippel-Lindau (VHL)-/- ccRCC, YAP also blocks nuclear factor {kappa}B (NF-{kappa}B) signaling in ccRCC to inhibit cancer cell growth under conditions where HIF2 is dispensable. Mechanistically, YAP inhibits the expression of Zinc fingers and homeoboxes 2 (ZHX2), a VHL substrate and critical co-factor of NF-{kappa}B in ccRCC. Furthermore, YAP competes with ZHX2 for binding to the NF-{kappa}B subunit p65. Consequently, elevated nuclear YAP blocks the cooperativity between ZHX2 and the NF-{kappa}B subunit p65, leading to diminished NF-{kappa}B target gene expression. Pharmacological inhibition of Hippo kinase blocked NF-{kappa}B transcriptional program and suppressed ccRCC cancer cell growth, which can be rescued by overexpression of ZHX2 or p65. Our study uncovers a crosstalk between the Hippo and NF-{kappa}B/ZHX2 pathways and its involvement in ccRCC growth inhibition, suggesting that targeting the Hippo pathway may provide a therapeutical opportunity for ccRCC treatment.