CTCF haploinsufficiency destabilizes DNA methylation and predisposes to cancer Academic Article uri icon

Overview

MeSH Major

  • DNA Methylation
  • Genes, Tumor Suppressor
  • Neoplasms
  • Repressor Proteins

abstract

  • Epigenetic alterations, particularly in DNA methylation, are ubiquitous in cancer, yet the molecular origins and the consequences of these alterations are poorly understood. CTCF, a DNA-binding protein that regulates higher-order chromatin organization, is frequently altered by hemizygous deletion or mutation in human cancer. To date, a causal role for CTCF in cancer has not been established. Here, we show that Ctcf hemizygous knockout mice are markedly susceptible to spontaneous, radiation-, and chemically induced cancer in a broad range of tissues. Ctcf(+/-) tumors are characterized by increased aggressiveness, including invasion, metastatic dissemination, and mixed epithelial/mesenchymal differentiation. Molecular analysis of Ctcf(+/-) tumors indicates that Ctcf is haploinsufficient for tumor suppression. Tissues with hemizygous loss of CTCF exhibit increased variability in CpG methylation genome wide. These findings establish CTCF as a prominent tumor-suppressor gene and point to CTCF-mediated epigenetic stability as a major barrier to neoplastic progression.

publication date

  • May 22, 2014

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC4040130

Digital Object Identifier (DOI)

  • 10.1016/j.celrep.2014.04.004

PubMed ID

  • 24794443

Additional Document Info

start page

  • 1020

end page

  • 9

volume

  • 7

number

  • 4