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Cancer Cell. 2017 May 8;31(5):653-668.e7. doi: 10.1016/j.ccell.2017.04.005.

CHD4 Has Oncogenic Functions in Initiating and Maintaining Epigenetic Suppression of Multiple Tumor Suppressor Genes.

Author information

1
Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; 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 710032, Shaanxi, China.
2
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 710032, Shaanxi, China.
3
Laboratory of Molecular Gerontology, National Institute on Aging, Baltimore, MD 21224, USA.
4
Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
5
Biomarkers and Alternative Models Branch, Division of Systems Biology, National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR 72079, USA.
6
Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD 21201, USA. Electronic address: frassool@som.umaryland.edu.
7
Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. Electronic address: sbaylin@jhmi.edu.

Abstract

An oncogenic role for CHD4, a NuRD component, is defined for initiating and supporting tumor suppressor gene (TSG) silencing in human colorectal cancer. CHD4 recruits repressive chromatin proteins to sites of DNA damage repair, including DNA methyltransferases where it imposes de novo DNA methylation. At TSGs, CHD4 retention helps maintain DNA hypermethylation-associated transcriptional silencing. CHD4 is recruited by the excision repair protein OGG1 for oxidative damage to interact with the damage-induced base 8-hydroxydeoxyguanosine (8-OHdG), while ZMYND8 recruits it to double-strand breaks. CHD4 knockdown activates silenced TSGs, revealing their role for blunting colorectal cancer cell proliferation, invasion, and metastases. High CHD4 and 8-OHdG levels plus low expression of TSGs strongly correlates with early disease recurrence and decreased overall survival.

KEYWORDS:

Chromodomain helicase DNA-binding protein 4; DNA methylation; DNA methyltransferase; colorectal cancer; double strand break; histone modification; metastases; nucleosome remodeling and histone deacetylation complex; oxidative damage; tumor suppressor gene

PMID:
28486105
PMCID:
PMC5587180
DOI:
10.1016/j.ccell.2017.04.005
[Indexed for MEDLINE]
Free PMC Article

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