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YAP targets TEAD4-NF-κB complex and inhibits ccRCC tumor growth

ABSTRACT: The prevalent understanding of Hippo signaling is one inhibitory pathway in tumor growth via deactivating the potential of YAP-TEAD transcriptional complex. The aberrant activation of YAP was observed in a series of human malignancies. However, recent studies implicate that in certain cancer types, YAP could be a tumor suppressor. Here, we reported a context-dependent function of YAP in clear cell renal carcinoma (ccRCC). Inhibition of Hippo kinase activity impeded ccRCC tumor growth and NF-κB transcriptional programs. Pharmacological blocking Hippo kinase activity or ectopic activation of YAP suppressed tumor growth in xenograft and PDX models. Mechanism studies revealed that TEAD could synchronize with P65 for NF-κB signaling activation, while YAP disrupted TEAD-NF-κB interactions and dissociated P65 from its target gene promoter, thereby inhibiting NF-κB transcriptional programs and ccRCC tumor growth. Our study identified a novel crosstalk between Hippo and NF-κB pathway, uncovered a non-canonical regulation of Hippo/YAP axis in renal cancer and suggested a novel strategy to ccRCC treatments by YAP activation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE252142 | GEO | 2024/05/31

REPOSITORIES: GEO

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Project description:Regulation of organ size is important for development and tissue homeostasis. In Drosophila, Hippo signaling controls organ size by regulating the activity of a TEAD transcription factor, Scalloped, through modulation of its coactivator protein Yki. The role of mammalian Tead proteins in growth regulation, however, remains unknown. Here we examined the role of mouse Tead proteins in growth regulation. In NIH3T3 cells, cell density and Hippo signaling regulated the activity of Tead proteins by modulating nuclear localization of a Yki homologue, Yap, and the resulting change in Tead activity altered cell proliferation. Tead2-VP16 mimicked Yap overexpression, including increased cell proliferation, reduced cell death, promotion of EMT, lack of cell contact inhibition, and promotion of tumor formation. Growth promoting activities of various Yap mutants correlated with their Tead-coactivator activities. Tead2-VP16 and Yap regulated largely overlapping sets of genes. However, only a few of the Tead/Yapregulated genes in NIH3T3 cells were affected in Tead1-/-;Tead2-/- or Yap-/- embryos. Most of the previously identified Yap-regulated genes were not affected in NIH3T3 cells or mutant mice. In embryos, levels of nuclear Yap and Tead1 varied depending on cell types. Strong nuclear accumulation of Yap and Tead1 were seen in myocardium, correlating with requirements of Tead1 for proliferation. However, their distribution did not always correlate with proliferation. Taken together, mammalian Tead proteins regulate cell proliferation and contact inhibition as a transcriptional mediator of Hippo signaling, but the mechanisms by which Tead/Yap regulate cell proliferation differ depending on cell types, and Tead, Yap and Hippo signaling may play multiple roles in mouse embryos. We used microarrays to know the gene expression profiles regurated by Tead2-VP16, Tead2-EnR, Yap, and cell density in NIH3T3 cells. Keywords: Cell density, genetic modification Tead2-VP16-, Tead2-EnR-, Yap- and control vector-expressing cells were cultured at low or high density for RNA extraction and hybridization on Affymetrix microarrays.

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YAP targets TEAD4-NF-κB complex and inhibits ccRCC tumor growth

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