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Oncofusion-driven de novo enhancer assembly promotes malignancy in Ewing sarcoma via aberrant expression of the stereociliary protein LOXHD1

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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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Main Authors: Deng, Qu (Author) , Natesan, Ramakrishnan (Author) , Cidre-Aranaz, Florencia (Author) , Arif, Shehbeel (Author) , Liu, Ying (Author) , Rasool, Reyaz ur (Author) , Wang, Pei (Author) , Mitchell-Velasquez, Erick (Author) , Das, Chandan Kanta (Author) , Vinca, Endrit (Author) , Cramer, Zvi (Author) , Grohar, Patrick J. (Author) , Chou, Margaret (Author) , Kumar-Sinha, Chandan (Author) , Weber, Kristy (Author) , Eisinger-Mathason, T. S. Karin (Author) , Grillet, Nicolas (Author) , Grünewald, Thomas G. P. (Author) , Asangani, Irfan A. (Author)
Format: Article (Journal)
Language:English
Published: 14 June 2022
In: Cell reports
Year: 2022, Volume: 39, Issue: 11, Pages: 1-26
ISSN:2211-1247
DOI:10.1016/j.celrep.2022.110971
Online Access: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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Author Notes: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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Summary: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.
Item Description:Gesehen am 03.08.2022
Physical Description:Online Resource
ISSN:2211-1247
DOI:10.1016/j.celrep.2022.110971

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