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- W3201996466 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 through an alternative transcription start site 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 short isoform expression and altered the EWSR1-FLI1 and HIF1a 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." @default.
- W3201996466 created "2021-10-11" @default.
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- W3201996466 date "2021-01-01" @default.
- W3201996466 modified "2023-09-27" @default.
- W3201996466 title "Oncofusion-Driven <i>de novo</i> Enhancer Assembly Promotes Malignancy in Ewing Sarcoma <i>via</i> Aberrant Expression of the Stereociliary Protein LOXHD1" @default.
- W3201996466 doi "https://doi.org/10.2139/ssrn.3931638" @default.
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