Nucleic Acids Research, 20 February 2019, DOI:  https://doi.org/10.1093/nar/gky1207

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

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

1 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, P.R. China, 

2 Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA, 

3 School of Biology and Basic Medical Sciences, Soochow University, Suzhou 215123, P.R. China, 

4 Cancer Science Institute of Singapore, National University of Singapore, 117599, Singapore, 

5 Department of Pathology, National University Hospital Singapore, 119074, Singapore, 

6 Department of Pathology and Laboratory Medicine, University of California Los Angeles and David Geffen School of Medicine, Los Angeles, CA 90095, USA, 

7 Department of Biochemistry and Molecular Biology, Medical College of Shantou University, Shantou 515041, P.R. China, 

8 Department of Oral & Maxillofacial Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, P.R. China, 

9 Department of Bioinformatics and Functional Genomics, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA and 

10 National University Cancer Institute, National University Hospital Singapore, 119074, Singapore

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.

文章链接：https://academic.oup.com/nar/article/47/3/1255/5212009