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

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

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.

MeSH terms

  • 8-Hydroxy-2'-Deoxyguanosine
  • Animals
  • Autoantigens / genetics*
  • Autoantigens / metabolism
  • Cell Movement
  • Cell Proliferation
  • Clustered Regularly Interspaced Short Palindromic Repeats
  • Colorectal Neoplasms / enzymology
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / pathology
  • Colorectal Neoplasms / surgery
  • DNA (Cytosine-5-)-Methyltransferases / genetics
  • DNA (Cytosine-5-)-Methyltransferases / metabolism
  • DNA Damage
  • DNA Glycosylases / genetics
  • DNA Glycosylases / metabolism
  • DNA Methylation*
  • Deoxyguanosine / analogs & derivatives
  • Deoxyguanosine / metabolism
  • Disease-Free Survival
  • Down-Regulation
  • Enhancer of Zeste Homolog 2 Protein / genetics
  • Enhancer of Zeste Homolog 2 Protein / metabolism
  • Epigenetic Repression*
  • Gene Expression Regulation, Neoplastic*
  • Gene Silencing*
  • Genes, Tumor Suppressor*
  • HCT116 Cells
  • Histocompatibility Antigens / genetics
  • Histocompatibility Antigens / metabolism
  • Histone-Lysine N-Methyltransferase / genetics
  • Histone-Lysine N-Methyltransferase / metabolism
  • Humans
  • Kaplan-Meier Estimate
  • Mi-2 Nucleosome Remodeling and Deacetylase Complex / genetics*
  • Mi-2 Nucleosome Remodeling and Deacetylase Complex / metabolism
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neoplasm Metastasis
  • Oxidative Stress
  • Proportional Hazards Models
  • RNA Interference
  • Receptors for Activated C Kinase
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism
  • Time Factors
  • Transcription, Genetic
  • Transfection
  • Tumor Suppressor Proteins

Substances

  • Autoantigens
  • CHD4 protein, human
  • Histocompatibility Antigens
  • Receptors for Activated C Kinase
  • Receptors, Cell Surface
  • Tumor Suppressor Proteins
  • ZMYND8 protein, human
  • 8-Hydroxy-2'-Deoxyguanosine
  • DNA (Cytosine-5-)-Methyltransferases
  • EHMT2 protein, human
  • EZH2 protein, human
  • Enhancer of Zeste Homolog 2 Protein
  • Histone-Lysine N-Methyltransferase
  • DNA Glycosylases
  • oxoguanine glycosylase 1, human
  • Mi-2 Nucleosome Remodeling and Deacetylase Complex
  • Deoxyguanosine