Abstract
As the second most common malignant bone tumor in children and adolescents, Ewing sarcoma is initiated and exacerbated by a chimeric oncoprotein, most commonly, EWS-FLI1. In this study, we apply epigenomic analysis to characterize the transcription dysregulation in this cancer, focusing on the investigation of super-enhancer and its associated transcriptional regulatory mechanisms. We demonstrate that super-enhancer-associated transcripts are significantly enriched in EWS-FLI1 target genes, contribute to the aberrant transcriptional network of the disease, and mediate the exceptional sensitivity of Ewing sarcoma to transcriptional inhibition. Through integrative analysis, we identify MEIS1 as a super-enhancer-driven oncogene, which co-operates with EWS-FLI1 in transcriptional regulation, and plays a key pro-survival role in Ewing sarcoma. Moreover, APCDD1, another super-enhancer associated gene, acting as a downstream target of both MEIS1 and EWS-FLI1, is also characterized as a novel tumor-promoting factor in this malignancy. These data delineate super-enhancer-mediated transcriptional deregulation in Ewing sarcoma, and uncover numerous candidate oncogenes which can be exploited for further understanding of the molecular pathogenesis for this disease.
Original language | American English |
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Pages (from-to) | 1255-12567 |
Number of pages | 11313 |
Journal | Nucleic Acids Research |
Volume | 47 |
Issue number | 3 |
DOIs | |
State | Published - 20 Feb 2019 |
Externally published | Yes |
Bibliographical note
Funding Information:National Research Foundation Singapore under its Singapore Translational Research Investigator Award [NMRC/STaR/0021/2014 to H.P.K.]; Singapore Ministry of Health's National Medical Research Council (NMRC); NMRC Centre Grant awarded to National University Cancer Institute; National Research Foundation Singapore and the Singapore Ministry of Education under its Research Centres of Excellence initiatives (to H.P.K.); Alan B. Slifka Foundation; Ewing's Sarcoma Research Foundation; National Natural Science Foundation of China (NSFC) [81802692, 81872306, 81872140, 81572484, 81420108026]; Guangzhou Bureau of Science and Information Technology [201704030036]. Funding for open access charge: National Natural Science Foundation of China (NSFC) [81802692, 81872306, 81872140, 81572484, 81420108026].
Funding Information:
National Research Foundation Singapore under its Singapore Translational Research Investigator Award [NMRC/STaR/0021/2014 to H.P.K.]; Singapore Ministry of Health’s National Medical Research Council (NMRC); NMRC Centre Grant awarded to National University Cancer Institute; National Research Foundation Singapore and the Singapore Ministry of Education under its Research Centres of Excellence initiatives (to H.P.K.); Alan B. Slifka Foundation; Ewing’s Sarcoma Research Foundation; National Natural Science Foundation of China (NSFC) [81802692, 81872306, 81872140, 81572484, 81420108026]; Guangzhou Bureau of Science and Information Technology [201704030036]. Funding for open access charge: National Natural Science Foundation of China (NSFC) [81802692, 81872306, 81872140, 81572484, 81420108026]. Conflict of interest statement. None declared.
Publisher Copyright:
© The Author(s) 2018.