{"doi":"10.1002/advs.202004846","title":"<i>SPOP</i> and <i>OTUD7A</i> Control <i>EWS–FLI1</i> Protein Stability to Govern Ewing Sarcoma Growth","abstract":"Chromosomal translocation results in development of an Ewing sarcoma breakpoint region 1-Friend leukemia integration 1 (EWS-FLI1) fusion oncogene in the majority of Ewing sarcoma. The persistent dependence of the tumor for this oncoprotein points to EWS-FLI1 as an ideal drug target. Although EWS-FLI1 transcriptional targets and binding partners are evaluated, the mechanisms regulating EWS-FLI1 protein stability remain elusive. Speckle-type POZ protein (SPOP) and OTU domain-containing protein 7A (OTUD7A) are identified as the bona fide E3 ligase and deubiquitinase, respectively, that control EWS-FLI1 protein turnover in Ewing sarcoma. Casein kinase 1-mediated phosphorylation of the VTSSS degron in the FLI1 domain enhances SPOP activity to degrade EWS-FLI1. Opposing this process, OTUD7A deubiquitinates and stabilizes EWS-FLI1. Depletion of OTUD7A in Ewing sarcoma cell lines reduces EWS-FLI1 protein abundance and impedes Ewing sarcoma growth in vitro and in mice. Performing an artificial-intelligence-based virtual drug screen of a 4-million small molecule library, 7Ai is identified as a potential OTUD7A catalytic inhibitor. 7Ai reduces EWS-FLI1 protein levels and decreases Ewing sarcoma growth in vitro and in a xenograft mouse model. This study supports the therapeutic targeting of OTUD7A as a novel strategy for Ewing sarcoma bearing EWS-FLI1 and related fusions, and may also be applicable to other cancers dependent on aberrant FLI1 expression.","journal":"Advanced Science","year":2021,"id":156265,"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":55,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9486,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":660408,"name":"Jianfeng Chen","orcid":"0000-0001-9732-7461","position":1,"is_corresponding":false},{"id":660409,"name":"Yao Jiang","orcid":"0000-0002-5244-8865","position":2,"is_corresponding":false},{"id":355833,"name":"Ying Wang","orcid":"0000-0002-1407-2668","position":3,"is_corresponding":false},{"id":661153,"name":"Tamara Vital","orcid":null,"position":4,"is_corresponding":false},{"id":535431,"name":"Jiaming Zhang","orcid":"0000-0001-8520-566X","position":5,"is_corresponding":false},{"id":593622,"name":"Christian Laggner","orcid":"0000-0002-8186-0891","position":6,"is_corresponding":false},{"id":493001,"name":"Kong T. Nguyen","orcid":null,"position":7,"is_corresponding":false},{"id":484229,"name":"Zhichuan Zhu","orcid":"0000-0003-0327-9978","position":8,"is_corresponding":false},{"id":661154,"name":"Alex W. Prevatte","orcid":null,"position":9,"is_corresponding":false},{"id":488554,"name":"Natalie K. Barker","orcid":"0000-0001-9248-2710","position":10,"is_corresponding":false},{"id":397771,"name":"Laura E. Herring","orcid":"0000-0003-4496-7312","position":11,"is_corresponding":false},{"id":13386,"name":"Ian J. Davis","orcid":"0000-0002-1552-0960","position":12,"is_corresponding":false},{"id":484232,"name":"Pengda Liu","orcid":"0000-0003-2755-3601","position":13,"is_corresponding":false},{"id":484228,"name":"Siyuan Su","orcid":"0000-0002-8816-9577","position":0,"is_corresponding":true}],"reference_count":64,"raw_metadata":null,"created_at":"2026-07-18T23:44:08.368845Z","pmid":"34060252","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":[]}