Class I and III HDACs and loss of active chromatin features contribute to epigenetic silencing of CDX1 and EPHB tumor suppressor genes in colorectal cancer

Epigenetics. 2011 May;6(5):610-22. doi: 10.4161/epi.6.5.15300. Epub 2011 May 1.

Abstract

Aberrant Wnt/β-catenin signaling is a driving force during initiation and progression of colorectal cancer. Yet, the Wnt/β-catenin targets CDX1, EPHB2, EPHB3 and EPHB4 (EPHB2-4) act as tumor suppressors in intestinal epithelial cells and frequently appear to be transcriptionally silenced in carcinomas. The molecular mechanisms which underlie the apparent loss of expression of a subset of Wnt/β-catenin targets in a background of persistent pathway activity are largely unknown. To gain insight into this, we quantified expression of CDX1 and EPHB2-4 in human tissue specimens of case-matched colorectal normal mucosa, adenoma and invasive carcinoma. In particular EPHB2-4 display biphasic, albeit not strictly coincident, expression profiles with elevated levels in adenomas and decreased transcription in approximately 30% of the corresponding carcinomas. Consistent with their divergent and variable expression we observed considerable heterogeneity among the epigenetic landscapes at CDX1 and EPHB2-4 in a model of colorectal carcinoma cell lines. Unlike the inactive CDX1 locus, EPHB2-4 maintain DNA hypomethylation of their promoter regions in the silent state. A strong reduction of active histone modifications consistently parallels reduced expression of CDX1 and EPHB3 and to some extent of EPHB2. Accordingly, treatment with inhibitors for DNA methyltransferases (DNMTs) and histone deacetylases (HDACs) restored CDX1 and EPHB2-4 expression depending upon epigenetic features at their promoters but also upon cellular background. Overall our findings show that downregulation of CDX1 and EphB receptor genes occurs independently and that different branches of epigenetic control systems including class I and III HDACs contribute to epigenetic silencing of Wnt/β-catenin targets during colorectal tumorigenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Chromatin / genetics*
  • Colorectal Neoplasms / genetics*
  • DNA Methylation / genetics
  • DNA Modification Methylases / antagonists & inhibitors
  • DNA Modification Methylases / genetics
  • Gene Expression Regulation, Neoplastic*
  • Gene Silencing
  • Genes, Tumor Suppressor*
  • HCT116 Cells
  • HEK293 Cells
  • HT29 Cells
  • Histone Deacetylases / genetics
  • Histone Deacetylases / metabolism*
  • Homeodomain Proteins / genetics*
  • Humans
  • Intestinal Mucosa / metabolism
  • Receptors, Eph Family / genetics*
  • Signal Transduction
  • Wnt Proteins / genetics
  • Wnt Proteins / metabolism
  • beta Catenin / genetics
  • beta Catenin / metabolism

Substances

  • CDX1 protein, human
  • Chromatin
  • Homeodomain Proteins
  • Wnt Proteins
  • beta Catenin
  • DNA Modification Methylases
  • Receptors, Eph Family
  • Histone Deacetylases