Suppression of ELF4 in ulcerative colitis predisposes host to colorectal cancer

Hongqiang Du; Huawei Xia; Tongtong Liu; Yingjie Li; Jilong Liu; Bingteng Xie; Jingxuan Chen; Tong Liu; Lili Cao; Shengde Liu; Siji Li; Peiyan Wang; Dandan Wang; Zeming Zhang; Yunfei Li; Xiaohuan Guo; Aiwen Wu; Mo Li; Fuping You

doi:10.1016/j.isci.2021.102169

Suppression of ELF4 in ulcerative colitis predisposes host to colorectal cancer

iScience. 2021 Feb 9;24(3):102169. doi: 10.1016/j.isci.2021.102169. eCollection 2021 Mar 19.

Authors

Hongqiang Du¹, Huawei Xia¹, Tongtong Liu¹, Yingjie Li², Jilong Liu³, Bingteng Xie^{4

5}, Jingxuan Chen¹, Tong Liu⁶, Lili Cao¹, Shengde Liu¹, Siji Li¹, Peiyan Wang¹, Dandan Wang¹, Zeming Zhang¹, Yunfei Li¹, Xiaohuan Guo⁷, Aiwen Wu², Mo Li^{4

5}, Fuping You¹

Affiliations

¹ Institute of Systems Biomedicine, Department of Immunology, School of Basic Medical Sciences, Beijing Key Laboratory of Tumor Systems Biology, Peking University Health Science Center, Beijing 100000, China.
² Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery, Peking University Cancer Hospital and Institute, Beijing 100000, China.
³ Department of surgical oncology, ChuiYangLiu Hospital affiliated to Tsinghua University, Beijing 100000, China.
⁴ Center for Reproductive Medicine, Peking University Third Hospital, Beijing 100000, China.
⁵ Key Laboratory of Assisted Reproduction, Ministry of Education, Beijing 100000, China.
⁶ College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing 163000, China.
⁷ Institute of Immunology, Tsinghua University School of Medicine, Beijing 100000, China.

Abstract

Ulcerative colitis (UC) is a chronic inflammatory bowel disease, characterized by relapsing and remitting colon mucosal inflammation. For patients suffering from UC, a higher risk of colon cancer has been widely recognized. Here, we found that Elf4 ^-/- mice developed colon tumors with 3 cycles of dextran sulfate sodium salt (DSS) treatment alone. We further showed that ELF4 suppression was prevalent in both patients with UC and DSS-induced mice models, and this suppression was caused by promoter region methylation. ELF4, upon PARylation by PARP1, transcriptionally regulated multiple DNA damage repair machinery components. Consistently, ELF4 deficiency leads to more severe DNA damage both in vitro and in vivo. Oral administration of montmorillonite powder can prevent the reduction of ELF4 in DSS-induced colitis models and lower the risk of colon tumor development during azoxymethane (AOM) and DSS induced colitis-associated cancer (CAC). These data provided additional mechanism of CAC initiation and supported the "epigenetic priming model of tumor initiation".

Keywords: Biochemistry; Molecular Biology; Transcriptomics.