Details

Autor(en) / Beteiligte

• Lin, Lehang
• Huang, Moli
• Shi, Xianping
• Mayakonda, Anand
• Hu, Kaishun
• Jiang, Yan-Yi
• Guo, Xiao
• Chen, Li
• Pang, Brendan
• Doan, Ngan
• Said, Jonathan W
• Xie, Jianjun
• Gery, Sigal
• Cheng, Xu
• Lin, Zhaoyu
• Li, Jinsong
• Berman, Benjamin P
• Yin, Dong
• Lin, De-Chen
• Koeffler, H Phillip

Titel

Super-enhancer-associated MEIS1 promotes transcriptional dysregulation in Ewing sarcoma in co-operation with EWS-FLI1

Ist Teil von

• Nucleic acids research, 2019-02, Vol.47 (3), p.1255

Ort / Verlag

England

Erscheinungsjahr

2019

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.