{Reference Type}: Journal Article
{Title}: YAP represses the TEAD-NF-κB complex and inhibits the growth of clear cell renal cell carcinoma.
{Author}: Li Z;Su P;Yu M;Zhang X;Xu Y;Jia T;Yang P;Zhang C;Sun Y;Li X;Yang H;Ding Y;Zhuang T;Guo H;Zhu J;
{Journal}: Sci Signal
{Volume}: 17
{Issue}: 843
{Year}: 2024 Jul 2
{Factor}: 9.517
{DOI}: 10.1126/scisignal.adk0231
{Abstract}: The Hippo pathway is generally understood to inhibit tumor growth by phosphorylating the transcriptional cofactor YAP to sequester it to the cytoplasm and reduce the formation of YAP-TEAD transcriptional complexes. Aberrant activation of YAP occurs in various cancers. However, we found a tumor-suppressive function of YAP in clear cell renal cell carcinoma (ccRCC). Using cell cultures, xenografts, and patient-derived explant models, we found that the inhibition of upstream Hippo-pathway kinases MST1 and MST2 or expression of a constitutively active YAP mutant impeded ccRCC proliferation and decreased gene expression mediated by the transcription factor NF-κB. Mechanistically, the NF-κB subunit p65 bound to the transcriptional cofactor TEAD to facilitate NF-κB-target gene expression that promoted cell proliferation. However, by competing for TEAD, YAP disrupted its interaction with NF-κB and prompted the dissociation of p65 from target gene promoters, thereby inhibiting NF-κB transcriptional programs. This cross-talk between the Hippo and NF-κB pathways in ccRCC suggests that targeting the Hippo-YAP axis in an atypical manner-that is, by activating YAP-may be a strategy for slowing tumor growth in patients.