Oncofusion-driven de novo enhancer assembly promotes malignancy in Ewing sarcoma via aberrant expression of the stereociliary protein LOXHD1
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 M. Chou, Chandan Kumar‐Sinha, Kristy Weber, T.S. Karin Eisinger‐Mathason, Nicolas Grillet, T. Grünewald, Irfan A. Asangani
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.