{"doi":"10.1101/2024.06.21.600079","title":"The Hippo pathway effector YAP inhibits NF-κB signaling and ccRCC growth by opposing ZHX2","abstract":"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 2α (HIF2α), a major oncogenic driver in Von Hippel-Lindau ( VHL ) -/- ccRCC, YAP also blocks nuclear factor κB (NF-κB) signaling in ccRCC to inhibit cancer cell growth under conditions where HIF2α is dispensable. Mechanistically, YAP inhibits the expression of Zinc fingers and homeoboxes 2 (ZHX2), a VHL substrate and critical co-factor of NF-κB in ccRCC. Furthermore, YAP competes with ZHX2 for binding to the NF-κB subunit p65. Consequently, elevated nuclear YAP blocks the cooperativity between ZHX2 and the NF-κB subunit p65, leading to diminished NF-κB target gene expression. Pharmacological inhibition of Hippo kinase blocked NF-κB 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-κB/ZHX2 pathways and its involvement in ccRCC growth inhibition, suggesting that targeting the Hippo pathway may provide a therapeutical opportunity for ccRCC treatment.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":499971,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9517,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":659738,"name":"Yong Suk Cho","orcid":"0000-0002-8828-3863","position":1,"is_corresponding":false},{"id":385240,"name":"Yuhong Han","orcid":"0000-0001-8933-4637","position":2,"is_corresponding":false},{"id":885760,"name":"Mengmeng Zhou","orcid":"0000-0002-4945-8632","position":3,"is_corresponding":false},{"id":628702,"name":"Yuchen Liu","orcid":"0000-0001-8922-9976","position":4,"is_corresponding":false},{"id":86690,"name":"Yingzi Yang","orcid":"0000-0003-3933-887X","position":5,"is_corresponding":false},{"id":628703,"name":"Shu Zhuo","orcid":"0000-0002-5728-5997","position":6,"is_corresponding":false},{"id":385242,"name":"Jin Jiang","orcid":"0000-0002-5951-372X","position":7,"is_corresponding":false},{"id":316646,"name":"Xu Li","orcid":"0000-0002-9401-6382","position":0,"is_corresponding":true}],"reference_count":45,"raw_metadata":null,"created_at":"2026-07-19T02:10:04.829419Z","pmid":"38979373","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}