Gene Silencing in Cancer by Histone H3 Lysine 27 Trimethylation Independent of Promoter DNA Methylation

Nat Genet. 2008 Jun;40(6):741-50. doi: 10.1038/ng.159. Epub 2008 May 18.

Abstract

Epigenetic silencing in cancer cells is mediated by at least two distinct histone modifications, polycomb-based histone H3 lysine 27 trimethylation (H3K27triM) and H3K9 dimethylation. The relationship between DNA hypermethylation and these histone modifications is not completely understood. Using chromatin immunoprecipitation microarrays (ChIP-chip) in prostate cancer cells compared to normal prostate, we found that up to 5% of promoters (16% CpG islands and 84% non-CpG islands) were enriched with H3K27triM. These genes were silenced specifically in prostate cancer, and those CpG islands affected showed low levels of DNA methylation. Downregulation of the EZH2 histone methyltransferase restored expression of the H3K27triM target genes alone or in synergy with histone deacetylase inhibition, without affecting promoter DNA methylation, and with no effect on the expression of genes silenced by DNA hypermethylation. These data establish EZH2-mediated H3K27triM as a mechanism of tumor-suppressor gene silencing in cancer that is potentially independent of promoter DNA methylation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Alkaline Phosphatase / metabolism
  • Biomarkers, Tumor / metabolism
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Cells, Cultured
  • Chromatin Immunoprecipitation
  • Colony-Forming Units Assay
  • CpG Islands
  • DNA Methylation*
  • DNA-Binding Proteins / antagonists & inhibitors
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Enhancer of Zeste Homolog 2 Protein
  • Female
  • Gene Silencing*
  • Histones / genetics*
  • Humans
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Lysine / chemistry
  • Lysine / genetics*
  • Male
  • Microarray Analysis
  • Microfilament Proteins / genetics
  • Microfilament Proteins / metabolism
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism
  • Polycomb Repressive Complex 2
  • Promoter Regions, Genetic / genetics*
  • Prostate / metabolism
  • Prostate / pathology
  • Prostatic Neoplasms / genetics*
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / pathology
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism

Substances

  • Biomarkers, Tumor
  • DNA-Binding Proteins
  • GAS2 protein, human
  • Histones
  • Microfilament Proteins
  • RNA, Messenger
  • Transcription Factors
  • EZH2 protein, human
  • Enhancer of Zeste Homolog 2 Protein
  • Polycomb Repressive Complex 2
  • Phosphatidylinositol 3-Kinases
  • Alkaline Phosphatase
  • Lysine