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

Deng, Qu; Natesan, Ramakrishnan; Cidre-Aranaz, Florencia; Arif, Shehbeel; Liu, Ying; Rasool, Reyaz ur; Wang, Pei; Mitchell-Velasquez, Erick; Das, Chandan Kanta; Vinca, Endrit; Cramer, Zvi; Grohar, Patrick J.; Chou, Margaret; Kumar-Sinha, Chandan; Weber, Kristy; Eisinger-Mathason, T. S. Karin; Grillet, Nicolas; Gruenewald, Thomas und Asangani, Irfan A. (2022): Oncofusion-driven de novo enhancer assembly promotes malignancy in Ewing sarcoma via aberrant expression of the stereociliary protein LOXHD1. In: Cell Reports, Vol. 39, No. 11, 110971

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 HIF1a 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 Type: Journal article
• Faculties: Medicine
• Subjects: 600 Technology > 610 Medicine and health
• ISSN: 2211-1247
• Language: English
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 458891500