YAP represses the TEAD-NF-κB complex and inhibits the growth of clear cell renal cell carcinoma.
Sci Signal
; 17(843): eadk0231, 2024 Jul 02.
Article
de En
| MEDLINE
| ID: mdl-38954637
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.
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Facteurs de transcription
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Néphrocarcinome
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Protein-Serine-Threonine Kinases
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Protéines adaptatrices de la transduction du signal
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Prolifération cellulaire
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Protéines de signalisation YAP
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Tumeurs du rein
Langue:
En
Journal:
Sci Signal
Sujet du journal:
CIENCIA
/
FISIOLOGIA
Année:
2024
Type de document:
Article