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

Abstract

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.

• Authors: 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
• Journal: Cell reports (Cell Rep) Vol. 39 Issue 11 Pg. 110971 (06 14 2022) ISSN: 2211-1247 [Electronic] United States
• PMID: 35705030 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.

Chemical References

• Carrier Proteins
• LOXHD1 protein, human
• Oncogene Proteins, Fusion
• Proteins
• Proto-Oncogene Protein c-fli-1
• RNA-Binding Protein EWS

Topics

• Adolescent
• Carrier Proteins (genetics)
• Cell Line, Tumor
• Child
• Enhancer Elements, Genetic
• Gene Expression Regulation, Neoplastic
• Humans
• Oncogene Proteins, Fusion (genetics, metabolism)
• Proteins (metabolism)
• Proto-Oncogene Protein c-fli-1 (genetics, metabolism)
• RNA-Binding Protein EWS (genetics, metabolism)
• Sarcoma, Ewing (genetics, pathology)