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Cancer Cell. 2019 Apr 15;35(4):633-648.e7. doi: 10.1016/j.ccell.2019.03.003. Epub 2019 Apr 4.

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

Author information

1
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
2
Department of Gastroenterology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province 430030, China; State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi Province 710032, China.
3
State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi Province 710032, China.
4
Center for Epigenetics, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
5
Center for Epigenetics, Van Andel Research Institute, Grand Rapids, MI 49503, USA. Electronic address: scott.rothbart@vai.org.
6
Department of Gastroenterology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province 430030, China; State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi Province 710032, China. Electronic address: xialimin@tjh.tjmu.edu.cn.
7
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Center for Epigenetics, Van Andel Research Institute, Grand Rapids, MI 49503, USA. Electronic address: sbaylin@jhmi.edu.

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.

KEYWORDS:

UHRF1; colorectal cancer prognosis; domain functions; maintenance DNA methylation; next-generation DNA demethylating agents; oncogenic properties; tumor suppressor gene silencing

PMID:
30956060
PMCID:
PMC6521721
[Available on 2020-04-15]
DOI:
10.1016/j.ccell.2019.03.003

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