UHRF1 facilitates the establishment and maintenance of DNA methylation patterns in mammalian cells. The establishment domains are defined, including E3 ligase function, but the maintenance domains are poorly characterized. Here, we demonstrate that UHRF1 histone- and hemimethylated DNA binding functions, but not E3 ligase activity, maintain cancer-specific DNA methylation in human colorectal cancer (CRC) cells. Disrupting either chromatin reader activity reverses DNA hypermethylation, reactivates epigenetically silenced tumor suppressor genes (TSGs), and reduces CRC oncogenic properties. Moreover, an inverse correlation between high UHRF1 and low TSG expression tracks with CRC progression and reduced patient survival. Defining critical UHRF1 domain functions and its relationship with CRC prognosis suggests directions for, and value of, targeting this protein to develop therapeutic DNA demethylating agents.
基金：
National Key Research and Development Program of China [2018YFC1312103]; National Natural Science Foundation of China [81522031, 81772623]; National Institute of Environmental Health Sciences, National Institutes of Health [R01ES011858]; NIH [R35GM124736]; American Cancer Society [PF1624501DMC]; Hodson Trust; Commonwealth Foundation
通讯机构：[1]Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Sch Med, Baltimore, MD 21287 USA[2]Huazhong Univ Sci & Technol, Dept Gastroenterol, Tongji Hosp Tongji Med Coll, Wuhan 430030, Hubei, Peoples R China[3]Fourth Mil Med Univ, State Key Lab Canc Biol, Natl Clin Res Ctr Digest Dis, Xian 710032, Shaanxi, Peoples R China[4]Fourth Mil Med Univ, Xijing Hosp Digest Dis, Xian 710032, Shaanxi, Peoples R China[5]Van Andel Res Inst, Ctr Epigenet, Grand Rapids, MI 49503 USA
推荐引用方式(GB/T 7714)：
Kong Xiangqian,Chen Jie,Xie Wenbing,et al.Defining UHRF1 Domains that Support Maintenance of Human Colon Cancer DNA Methylation and Oncogenic Properties[J].CANCER CELL.2019,35(4):633-+.doi:10.1016/j.ccell.2019.03.003.
APA：
Kong, Xiangqian,Chen, Jie,Xie, Wenbing,Brown, Stephen M.,Cai, Yi...&Baylin, Stephen B..(2019).Defining UHRF1 Domains that Support Maintenance of Human Colon Cancer DNA Methylation and Oncogenic Properties.CANCER CELL,35,(4)
MLA：
Kong, Xiangqian,et al."Defining UHRF1 Domains that Support Maintenance of Human Colon Cancer DNA Methylation and Oncogenic Properties".CANCER CELL 35..4(2019):633-+
医学