Nucleic Acids Res. 2020 Nov 18;48(20):11434-11451. doi: 10.1093/nar/gkaa901.

EWS-FLI1 regulates and cooperates with core regulatory circuitry in Ewing sarcoma.

Yuning Liao, Yuan Liu, Zhenlong Shao, Xiaohong Xia, Yuanfei Deng, Jianyu Cai, Leyi Yao, Jinchan He, Cuifu Yu, Tumei Hu, Wenshuang Sun, Fang Liu, Daolin Tang, Jinbao Liu & Hongbiao Huang

1 Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation; State Key Laboratory of Respiratory Disease; Affiliated Cancer Hospital of Guangzhou Medical University; Sino-French Hoffmann institute, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou 510120, P.R. China.

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

3 Departments of Surgery and Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.

4 Cancer Science Institute of Singapore, National University of Singapore, Singapore 117600, Singapore.

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

6 National University Cancer Institute, National University Hospital Singapore, Singapore 119074, Singapore.

Core regulatory circuitry (CRC)-dependent transcriptional network is critical for developmental tumors in children and adolescents carrying few gene mutations. However, whether and how CRC contributes to transcription regulation in Ewing sarcoma is unknown. Here, we identify and functionally validate a CRC 'trio' constituted by three transcription factors (TFs): KLF15, TCF4 and NKX2-2, in Ewing sarcoma cells. Epigenomic analyses demonstrate that EWS-FLI1, the primary fusion driver for this cancer, directly establishes super-enhancers of each of these three TFs to activate their transcription. In turn, KLF15, TCF4 and NKX2-2 co-bind to their own and each other's super-enhancers and promoters, forming an inter-connected auto-regulatory loop. Functionally, CRC factors contribute significantly to cell proliferation of Ewing sarcoma both in vitro and in vivo. Mechanistically, CRC factors exhibit prominent capacity of co-regulating the epigenome in cooperation with EWS-FLI1, occupying 77.2% of promoters and 55.6% of enhancers genome-wide. Downstream, CRC TFs coordinately regulate gene expression networks in Ewing sarcoma, controlling important signaling pathways for cancer, such as lipid metabolism pathway, PI3K/AKT and MAPK signaling pathways. Together, molecular characterization of the oncogenic CRC model advances our understanding of the biology of Ewing sarcoma. Moreover, CRC-downstream genes and signaling pathways may contain potential therapeutic targets for this malignancy.

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