WITHDRAWN: EP300 promotes tumor development and correlates with poor prognosis in esophageal squamous carcinoma

// Yanghui Bi 1, 2, 3, * , Ling Zhang 1, 2, 3, 4, * , Heyang Cui 1, 2, 3, * , Pengzhou Kong 1, 2, 3, * , Ting Yan 1, 2, 3 , Jiayi Li 5 , Zianyi Wang 6 , Caixia Cheng 1, 2, 3, 7 , Bin Song 1, 2, 3, 8 , Bin Yang 1, 2, 3, 9 , Enwei Xu 1, 2, 3, 10 , Jie Yang 1, 2, 3 , Xiaoling Hu 1, 2, 3, 11 , Ruyi Shi 1, 2, 3, 12 , Yu Qian 1, 2, 3 , Fang Wang 1, 2, 3 , Hongyi Li 1, 2, 3 , Zhiwu Jia 1, 2, 3 , Yanchun Ma 1, 2, 3 , Jian Yang 1, 2, 3 , Yike Li 1, 2, 3 , Juan Wang 1, 2, 3 , Yiqian Liu 1, 2, 3 , Yuanfang Zhai 1, 2, 3 , Lu Chang 1, 2, 3 , Yi Wang 1, 2, 3 , Yingchun Zhang 1, 2, 3 , Feng Liu 13 , Haiyan Liu 1, 2, 3, 14 , Yanyan Zhang 1, 2, 3, 15 , Jing Liu 1, 2, 3, 15 , Xiaolong Cheng 1, 2, 3, 16 and Yongping Cui 1, 2, 3 1 Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China 2 Key Laboratory of Carcinogenesis and Translational Research of Esophageal Cancer, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China 3 Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China 4 Department of Pathology, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China 5 Anglo-Chinese School (Independent), Singapore 6 Taiyuan Lingde Secondary School, Taiyuan, Shanxi 030001, PR China 7 Department of Pathology, The First Hospital, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China 8 Department of Oncology, The First Hospital, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China 9 Department of General Surgery, Shanxi Cancer Hospital, Taiyuan, Shanxi 030001, PR China 10 Department of Pathology, Shanxi Cancer Hospital, Taiyuan, Shanxi 030001, PR China 11 Department of Pharmacology, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China 12 Department of Cell Biology and Genetics, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China 13 Department of Forensic, Shanxi Medical University, Taiyuan, Shanxi 030001, China 14 Department of Nuclear Medicine, The First Hospital, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China 15 Department of General Surgery, The First Hospital, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China 16 Department of Anatomy, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China * These authors contributed equally to this work Correspondence to: Yongping Cui, email: cuiyp@sxmu.edu.cn Keywords: EP300; ESCC; prognosis; angiogenesis; EMT Received: August 21, 2017      Accepted: October 29, 2017      Published: January 02, 2018 ABSTRACT Recently, genomic sequencing research identified a range of mutations in genes encoding proteins involved in histone modifications in human cancers. Here, we integrated genomic sequencing data from 325 esophageal squamous cell carcinoma (ESCC) cases and screened a series of frequently mutated histone modifier genes, including MLL2, EP300, RB1 and KDM6A. Of them, EP300 was not only a significantly mutated gene but also a highly frequently mutated gene with mutation frequency more than 10% in ESCC. We found that EP300 mutation was associated with tumor grade, pathological T stage and lymph node metastasis, predicting a shorter cumulative survival status. Further immunohistochemical analysis based on tissue microarray showed that EP300 expression was significantly higher in ESCC tumor tissues, and the expression levels were associated with poor survival of ESCC patients. Moreover, we found that EP300 knockdown led to inhibition of cell proliferation and colony formation, as well as cell migration and invasion. Combined the results of RNA-sequencing with validation test, EP300 knockdown led to a significant change in expression of genes associated with angiogenesis, hypoxia and epithelial mesenchymal transition. In particular, angiogenesis network included up-regulation of SERPINF1 and down-regulation of FGF2, FLT1, CCL2. In hypoxia network, core genes included down-regulated LDHA, ADM, SLC2A1 and CA9. EMT network covered the up-regulation of E-cadherin and down-regulation of N-cadherin, Snail and Vimentin. Taken together, our study identified a novel role and mechanism of EP300 in ESCC and provided epigenetic therapeutic strategies for the treatment of ESCC.