Defining UHRF1 domains that support maintenance of human colon cancer DNA methylation and oncogenic properties
Authors: Xiangqian Kong, Jie Chen, Wenbing Xie, Stephen M. Brown, Yi Cai, Kaichun Wu, Daiming Fan, Yongzhan Nie, Srinivasan Yegnasubramanian, Rochelle L. Tiedemann, Yong Tao, Ray-Whay Chiu Yen, Michael J. Topper, Cynthia A. Zahnow, Hariharan Easwaran, Scott B. Rothbart, Limin Xia, Stephen B. Baylin
Summary:
UHRF1 facilitates the establishment and maintenance of DNA methylation patterns inmammalian cells. The establishment domains are defined, including E3 ligase function,but the maintenance domains are poorly characterized. Here, we demonstrate that UHRF1histone- and hemimethylated DNA binding functions, but not E3 ligase activity, maintaincancer-specific DNA methylation in human colorectal cancer (CRC) cells. Disruptingeither chromatin reader activity reverses DNA hypermethylation, reactivates epigeneticallysilenced tumor suppressor genes (TSGs), and reduces CRC oncogenic properties. Moreover,an inverse correlation between high UHRF1 and low TSG expression tracks with CRC progressionand reduced patient survival. Defining critical UHRF1 domain functions and its relationshipwith CRC prognosis suggests directions for, and value of, targeting this protein todevelop therapeutic DNA demethylating agents.
Source: Cancer Cell, 2019
Summary:
UHRF1 facilitates the establishment and maintenance of DNA methylation patterns inmammalian cells. The establishment domains are defined, including E3 ligase function,but the maintenance domains are poorly characterized. Here, we demonstrate that UHRF1histone- and hemimethylated DNA binding functions, but not E3 ligase activity, maintaincancer-specific DNA methylation in human colorectal cancer (CRC) cells. Disruptingeither chromatin reader activity reverses DNA hypermethylation, reactivates epigeneticallysilenced tumor suppressor genes (TSGs), and reduces CRC oncogenic properties. Moreover,an inverse correlation between high UHRF1 and low TSG expression tracks with CRC progressionand reduced patient survival. Defining critical UHRF1 domain functions and its relationshipwith CRC prognosis suggests directions for, and value of, targeting this protein todevelop therapeutic DNA demethylating agents.
Source: Cancer Cell, 2019