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National Institute of Environmental Health Sciences

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Your Environment. Your Health.

Publication Detail

Title: Defining UHRF1 Domains that Support Maintenance of Human Colon Cancer DNA Methylation and Oncogenic Properties.

Authors: Kong, Xiangqian; Chen, Jie; Xie, Wenbing; Brown, Stephen M; Cai, Yi; Wu, Kaichun; Fan, Daiming; Nie, Yongzhan; Yegnasubramanian, Srinivasan; Tiedemann, Rochelle L; Tao, Yong; Chiu Yen, Ray-Whay; Topper, Michael J; Zahnow, Cynthia A; Easwaran, Hariharan; Rothbart, Scott B; Xia, Limin; Baylin, Stephen B

Published In Cancer Cell, (2019 04 15)

Abstract: 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.

PubMed ID: 30956060 Exiting the NIEHS site

MeSH Terms: Animals; CCAAT-Enhancer-Binding Proteins/genetics; CCAAT-Enhancer-Binding Proteins/metabolism*; Caco-2 Cells; Colorectal Neoplasms/enzymology*; Colorectal Neoplasms/genetics; Colorectal Neoplasms/metabolism; Colorectal Neoplasms/pathology; CpG Islands; DNA Methylation*; Epigenesis, Genetic*; Female; Gene Expression Regulation, Neoplastic; HCT116 Cells; HT29 Cells; Histones/genetics; Histones/metabolism; Humans; Male; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, Nude; Mice, SCID; Mutation; Neoplasm Metastasis; PHD Zinc Fingers; Prognosis; Time Factors; Ubiquitin-Protein Ligases/genetics; Ubiquitin-Protein Ligases/metabolism*

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