Oncofusion-driven de novo enhancer assembly promotes malignancy in Ewing sarcoma via aberrant expression of the stereociliary protein LOXHD1
Ewing sarcoma (EwS) is a highly aggressive tumor of bone and soft tissues that mostly affects children and adolescents. The pathognomonic oncofusion EWSR1::FLI1 transcription factor drives EwS by orchestrating an oncogenic transcription program through de novo enhancers. By integrative analysis of t...
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| Hauptverfasser: | , , , , , , , , , , , , , , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
14 June 2022
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| In: |
Cell reports
Year: 2022, Jahrgang: 39, Heft: 11, Pages: 1-26 |
| ISSN: | 2211-1247 |
| DOI: | 10.1016/j.celrep.2022.110971 |
| Online-Zugang: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.celrep.2022.110971 Verlag, lizenzpflichtig, Volltext: https://www.sciencedirect.com/science/article/pii/S2211124722007574 
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| Verfasserangaben: | Qu Deng, Ramakrishnan Natesan, Florencia Cidre-Aranaz, Shehbeel Arif, Ying Liu, Reyaz ur Rasool, Pei Wang, Erick Mitchell-Velasquez, Chandan Kanta Das, Endrit Vinca, Zvi Cramer, Patrick J. Grohar, Margaret Chou, Chandan Kumar-Sinha, Kristy Weber, T.S. Karin Eisinger-Mathason, Nicolas Grillet, Thomas G.P. Grünewald, Irfan A. Asangani |
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| 245 | 1 | 0 | |a Oncofusion-driven de novo enhancer assembly promotes malignancy in Ewing sarcoma via aberrant expression of the stereociliary protein LOXHD1 |c Qu Deng, Ramakrishnan Natesan, Florencia Cidre-Aranaz, Shehbeel Arif, Ying Liu, Reyaz ur Rasool, Pei Wang, Erick Mitchell-Velasquez, Chandan Kanta Das, Endrit Vinca, Zvi Cramer, Patrick J. Grohar, Margaret Chou, Chandan Kumar-Sinha, Kristy Weber, T.S. Karin Eisinger-Mathason, Nicolas Grillet, Thomas G.P. Grünewald, Irfan A. Asangani |
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| 520 | |a Ewing sarcoma (EwS) is a highly aggressive tumor of bone and soft tissues that mostly affects children and adolescents. The pathognomonic oncofusion EWSR1::FLI1 transcription factor drives EwS by orchestrating an oncogenic transcription program through de novo enhancers. By integrative analysis of thousands of transcriptomes representing pan-cancer cell lines, primary cancers, metastasis, and normal tissues, we identify a 32-gene signature (ESS32 [Ewing Sarcoma Specific 32]) that stratifies EwS from pan-cancer. Among the ESS32, LOXHD1, encoding a stereociliary protein, is the most highly expressed gene through an alternative transcription start site. Deletion or silencing of EWSR1::FLI1 bound upstream de novo enhancer results in loss of the LOXHD1 short isoform, altering EWSR1::FLI1 and HIF1α pathway genes and resulting in decreased proliferation/invasion of EwS cells. These observations implicate LOXHD1 as a biomarker and a determinant of EwS metastasis and suggest new avenues for developing LOXHD1-targeted drugs or cellular therapies for this deadly disease. | ||
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