Overexpression of the transcription factor ATF3 with a regulatory molecular signature associates with the pathogenic development of colorectal cancer

// Feng Yan 1, 2, * , Le Ying 1, 3, * , Xiaofang Li 1, 2 , Bin Qiao 1, 4 , Qiaohong Meng 2 , Liang Yu 5 , Xiangliang Yuan 1 , Shu-Ting Ren 6 , David W. Chan 7 , Liyun Shi 8 , Peihua Ni 1 , Xuefeng Wang 9 , Dakang Xu 1, 2, 10, 11 and Yiqun Hu 1, 9 1 Faculty of Medical Laboratory Science, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China 2 Institute of Ageing Research, Hangzhou Normal University School of Medicine, Hangzhou, China 3 Department of Tea Science, Zhejiang University, Hangzhou, China 4 Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China 5 Department of General Surgery, Shanghai Jiao Tong University Affiliated First People’s Hospital, Shanghai, China, 6 Department of Pathology, School of Basic Medical Science, Xi’an Jiaotong University Health Science Center, Xi’an, China 7 Department of Obstetrics and Gynaecology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, P.R. China 8 Department of Microbiology and Immunology, Nanjing University of Chinese Medicine, Nanjing, China 9 Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China 10 Hudson Institute of Medical Research, Clayton, Victoria, Australia 11 Department of Molecular and Translational Science, Monash University, Clayton, Victoria, Australia * Feng Yan and Le Ying contributed equally to this work Correspondence to: Yiqun Hu, email: ichunhu@126.com Dakang Xu, email: dakang.xu@monash.edu Keywords: colorectal cancer, ATF3, genes signature, prognosis Received: January 25, 2017     Accepted: March 08, 2017     Published: March 29, 2017 ABSTRACT The identification of novel biomarkers of cancer is important for improved diagnosis and prognosis. With an abundant amount of resources in the publicly available database, such as the Cancer Genome Atlas (TCGA) database, an integrative strategy is used to systematically characterize the aberrant patterns of colorectal cancer (CRC) based on RNA-Seq, chromatin immunoprecipitation sequencing (ChIP-Seq), tissue microarray (TMA), gene profiling and molecular signatures. The expression of the transcription factor ATF3 was elevated in human CRC specimens in a TMA by immunochemistry analysis compared to the adjacent normal tissues. In addition, ATF3 overexpression associated with a regulatory molecular signature, and its functions are related to the pathogenic development of CRC. Furthermore, putative ATF3 regulatory elements were identified within the promoters of ATF3 target genes and were confirmed by ChIP-Seq. Critically, in higher ATF3 expression cell lines (HCT116 and RKO) with CRISPR/Cas9 mediated ATF3 knock out, we are able to show that ATF3 target genes such as CEACAM1, DUSP14, HDC, HLF and ULBP2 , are required for invasion and proliferation, and they are robustly linked with poor prognosis in CRC. Our findings have important implications for CRC tumorigenesis and may be exploited for diagnostic and therapeutic purposes.