{"doi":"10.1101/2021.02.22.432287","title":"Oncofusion-driven <i>de novo</i> enhancer assembly promotes malignancy in Ewing sarcoma <i>via</i> aberrant expression of the stereociliary protein LOXHD1","abstract":"Abstract Ewing Sarcoma (EwS) is a highly aggressive tumor of bone and soft tissues that mostly affects children and adolescents. The pathognomonic oncofusion EWSR1-ETS (EWSR1-FLI1/EWSR1-ERG) transcription factors drive EwS by orchestrating an oncogenic transcription program through de novo enhancers. Pharmacological targeting of these oncofusions has been challenged by unstructured prion-like domains and common DNA binding domains in the EWSR1 and ETS protein, respectively. Alternatively, identification and characterization of mediators and downstream targets of EWSR1-FLI1 dependent or independent function could offer novel therapeutic options. By integrative analysis of thousands of transcriptome datasets representing pan-cancer cell lines, primary cancer, metastasis, and normal tissues, we have identified a 32 gene signature (ESS32 - Ewing Sarcoma Specific 32) that could stratify EwS from pan-cancer. Of the ESS32, LOXHD1 – that encodes a stereociliary protein, was the most exquisitely expressed gene in EwS. CRISPR-Cas9 mediated deletion or silencing of EWSR1-FLI1 bound upstream de novo enhancer elements in EwS cells led to the loss of LOXHD1 expression and altered the EWSR1-FLI1, MYC, and HIF1α pathway genes, resulting in decreased proliferation and invasion in vitro and in vivo . These observations implicate LOXHD1 as a novel biomarker and a major determinant of EwS metastasis and open up new avenues for developing LOXHD1-targeted drugs or cellular therapies for this deadly disease.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":220297,"datarank":0.10397207708399181,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.0,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9556,"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":273889,"name":"Ramakrishnan Natesan","orcid":"0000-0002-7888-9255","position":1,"is_corresponding":false},{"id":819820,"name":"Florencia Cidre‐Aranaz","orcid":"0000-0002-0246-7179","position":2,"is_corresponding":false},{"id":819821,"name":"Shehbeel Arif","orcid":"0000-0002-0358-6866","position":3,"is_corresponding":false},{"id":604816,"name":"Ying Liu","orcid":"0000-0003-0802-3832","position":4,"is_corresponding":false},{"id":565645,"name":"Reyaz ur Rasool","orcid":"0009-0001-5530-682X","position":5,"is_corresponding":false},{"id":506749,"name":"Pei Wang","orcid":"0000-0002-0538-7641","position":6,"is_corresponding":false},{"id":819822,"name":"Zvi Cramer","orcid":"0000-0002-7386-3937","position":7,"is_corresponding":false},{"id":701121,"name":"Margaret M. Chou","orcid":"0000-0003-0500-0715","position":8,"is_corresponding":false},{"id":51858,"name":"Chandan Kumar‐Sinha","orcid":"0000-0002-8696-3400","position":9,"is_corresponding":false},{"id":819823,"name":"Kristy Weber","orcid":"0000-0001-8021-011X","position":10,"is_corresponding":false},{"id":810295,"name":"T.S. Karin Eisinger‐Mathason","orcid":"0000-0003-4959-3671","position":11,"is_corresponding":false},{"id":511368,"name":"Nicolas Grillet","orcid":"0000-0001-8007-9246","position":12,"is_corresponding":false},{"id":273628,"name":"Thomas G. P. Grünewald","orcid":"0000-0003-0920-7377","position":13,"is_corresponding":false},{"id":273893,"name":"Irfan A. Asangani","orcid":"0000-0001-5381-1702","position":14,"is_corresponding":false},{"id":565644,"name":"Qu Deng","orcid":"0000-0003-0030-2511","position":0,"is_corresponding":true}],"reference_count":60,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:53:46.965811Z","pmid":null,"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":[]}