期刊
CELL REPORTS
卷 39, 期 11, 页码 -出版社
CELL PRESS
DOI: 10.1016/j.celrep.2022.110971
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资金
- Hayman Family Foundation
- Sarcoma Foundation of America Research Award
- National Institute on Deafness and other Communication Disorders (NIDCD) [R01 DC016409-01A1, 1R21DC019457-01]
- OHNS startup funding
- Oberndorf family
- Stanford Initiative to Cure Hearing Loss
- Dr. Leopold and Carmen Ellinger Foundation
- Dr. Rolf M. Schwiete Foundation
- German Cancer Aid [DKH-70112257, DKH-70114111]
- Gert und Susanna Mayer Foundation
- SMARCB1 association
- Boehringer Ingelheim Foundation
- Matthias-Lackas Foundation
- Deutsche Forschungsgemeinschaft [DFG458891500]
- Ministry of Education and Science (BMBF) [MSCoreSys-014]
- Barbara and Wilfried Mohr Foundation
Through transcriptome analysis, researchers identified a 32-gene signature that distinguishes Ewing sarcoma from other cancers. The LOXHD1 gene, which is highly expressed, is transcribed through an alternative transcription start site. Deleting or silencing the transcription factor associated with Ewing sarcoma leads to loss of the LOXHD1 short isoform, affecting tumor cell proliferation and invasion.
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.
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