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

Area of Science:

• Oncology
• Molecular Biology
• Cell Signaling

Background:

• The Hippo signaling pathway is generally considered a tumor suppressor, inhibiting pathway effectors Yes1 associated transcriptional regulator (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ).
• YAP's role can be context-dependent, acting as a tumor suppressor in certain cancers like clear cell renal cell carcinomas (ccRCC).
• Hypoxia-inducible factor 2α (HIF2α) is a key oncogenic driver in Von Hippel-Lindau (VHL)-/- ccRCC.

Purpose of the Study:

• To investigate the role of YAP in ccRCC, beyond its known inhibition of HIF2α.
• To elucidate the mechanisms by which YAP suppresses ccRCC growth.
• To explore the potential of targeting the Hippo pathway for ccRCC therapy.

Main Methods:

• Investigated YAP's effect on nuclear factor κB (NF-κB) signaling in ccRCC.
• Analyzed the interaction between YAP, Zinc fingers and homeoboxes 2 (ZHX2), and NF-κB subunit p65.
• Utilized pharmacological inhibition of Hippo kinase and gene overexpression (ZHX2, p65) in ccRCC cell models.

Main Results:

• YAP inhibits both HIF2α and NF-κB signaling in ccRCC.
• YAP suppresses ccRCC growth by inhibiting ZHX2 expression and competing with ZHX2 for p65 binding, thereby diminishing NF-κB target gene expression.
• Pharmacological inhibition of Hippo kinase suppressed ccRCC growth, an effect reversible by ZHX2 or p65 overexpression.

Conclusions:

• A novel crosstalk between the Hippo and NF-κB/ZHX2 pathways in ccRCC is uncovered.
• YAP functions as a tumor suppressor in ccRCC by inhibiting the NF-κB/ZHX2 axis.
• Targeting the Hippo pathway presents a potential therapeutic strategy for ccRCC treatment.