Abnormal Activations of Super-Enhancers Enhance the Carcinogenicity in Lung Adenocarcinoma

Jianlong Zhou,1,2,* Dingxue Wang,3,* Dongxin Tang,3 Wenhua Huang1 1Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, People’s Republic of China; 2Department of Oncology, The Affiliated Xinhui Hospital, Southern Medical University, Xinhui, People’s Republic of China; 3Department of Oncology, The First Affiliated Hospital, Guizhou University of Traditional Chinese Medicine, Guiyang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Dongxin TangThe First Affiliated Hospital, Guizhou University of Traditional Chinese Medicine, No. 71 Baoshanbei Road, Guiyang 550000, People’s Republic of ChinaEmail tangdongxin@sina.comWenhua HuangDepartment of Oncology, Zhujiang Hospital, Southern Medical University, No.253 Gongye Middle Avenue, Guangzhou 510280, People’s Republic of ChinaEmail huangwenhua88888@outlook.comBackground: Lung tumors and normal lung tissues show large differences in epigenetic modification which can affect the chromosome structure and expression of genes. However, the epigenetic reprogramming in lung adenocarcinoma remains unclear.Methods and Results: With the bioinformatics analysis, we found that some activated super-enhancers (SEs) only appear in lung adenocarcinoma cells, and 781 abnormal activated super-enhancers (AASEs) were found. Not only are the traditional oncogenes found to be activated by AASEs, such as MET and SLC2A1, but also some new genes were activated by AASEs, which probably contributes to the carcinogenic process in lung cancer. The enrichment analysis of the genes activated by AASEs shows that the glycolysis process and cell proliferation were enhanced and the apoptotic process was negatively regulated. Two AASEs were separately knockout by CRISPR/Cas9 in A549, PC-9, and H1299 cell lines and the expression of target genes decreased. The motif of CTCF, SMARCA1, SOX4, FOXM1, IRF3, IRF7, and STAT2 was enriched in AASEs, supporting that the chromosome structure changed and these transcription factors would be the master regulators on the formation of AASEs.Conclusion: This study provided comprehensive insight into the mechanisms of SEs, as well as a potential therapeutic target for lung cancer.Keywords: lung adenocarcinoma, epigenetic, super-enhancer, transcription factors