{"doi":"10.1038/s41467-024-45280-5","title":"ASPSCR1-TFE3 reprograms transcription by organizing enhancer loops around hexameric VCP/p97","abstract":"The t(X,17) chromosomal translocation, generating the ASPSCR1::TFE3 fusion oncoprotein, is the singular genetic driver of alveolar soft part sarcoma (ASPS) and some Xp11-rearranged renal cell carcinomas (RCCs), frustrating efforts to identify therapeutic targets for these rare cancers. Here, proteomic analysis identifies VCP/p97, an AAA+ ATPase with known segregase function, as strongly enriched in co-immunoprecipitated nuclear complexes with ASPSCR1::TFE3. We demonstrate that VCP is a likely obligate co-factor of ASPSCR1::TFE3, one of the only such fusion oncoprotein co-factors identified in cancer biology. Specifically, VCP co-distributes with ASPSCR1::TFE3 across chromatin in association with enhancers genome-wide. VCP presence, its hexameric assembly, and its enzymatic function orchestrate the oncogenic transcriptional signature of ASPSCR1::TFE3, by facilitating assembly of higher-order chromatin conformation structures demonstrated by HiChIP. Finally, ASPSCR1::TFE3 and VCP demonstrate co-dependence for cancer cell proliferation and tumorigenesis in vitro and in ASPS and RCC mouse models, underscoring VCP's potential as a novel therapeutic target.","journal":"Nature Communications","year":2024,"id":436152,"datarank":0.5436189305193738,"base_score":2.4849066497880004,"endowment":2.4849066497880004,"self_citation_contribution":0.37273599746820013,"citation_network_contribution":0.17088293305117366,"self_endowment_contribution":0.37273599746820013,"citer_contribution":0.17088293305117366,"corpus_percentile":null,"corpus_rank":null,"citation_count":11,"citer_count":9,"citers_with_citation_signal":8,"citers_with_endowment":8,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9547,"is_data_producer":true,"deposit_databanks":{"GEO":["GSE162609"]},"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":692766,"name":"Li Li","orcid":"0000-0002-1802-3126","position":1,"is_corresponding":false},{"id":1173696,"name":"Shiv Prakash Verma","orcid":null,"position":2,"is_corresponding":false},{"id":207078,"name":"Shuxin Wang","orcid":"0000-0003-0403-3953","position":3,"is_corresponding":false},{"id":692765,"name":"Jared J. 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