CTCF haploinsufficiency destabilizes DNA methylation and predisposes to cancer

Cell Rep. 2014 May 22;7(4):1020-9. doi: 10.1016/j.celrep.2014.04.004. Epub 2014 May 1.


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 types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • CCCTC-Binding Factor
  • Cell Line, Tumor
  • DNA Methylation*
  • Epigenesis, Genetic
  • Gene Expression Regulation, Neoplastic
  • Genes, Tumor Suppressor*
  • Genetic Predisposition to Disease
  • Haploinsufficiency
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mutation
  • Neoplasms / genetics*
  • Neoplasms / metabolism
  • Protein Binding
  • Repressor Proteins / genetics*
  • Repressor Proteins / metabolism
  • Survival Analysis


  • CCCTC-Binding Factor
  • CTCF protein, human
  • Ctcf protein, mouse
  • Repressor Proteins

Associated data

  • GEO/GSE48975