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

Limin Xia, Wenjie Huang, Marina Bellani, Michael M. Seidman, Kaichun Wu, Daiming Fan, Yongzhan Nie, Yi Cai, Yang W. Zhang, Li Rong Yu, Huili Li, Cynthia A. Zahnow, Wenbing Xie, Ray Whay Chiu Yen, Feyruz V. Rassool, Stephen B. Baylin

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)653-668.e7
JournalCancer cell
Volume31
Issue number5
DOIs
StatePublished - May 8 2017

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

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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