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Title: CTCF haploinsufficiency destabilizes DNA methylation and predisposes to cancer.

Authors: Kemp, Christopher J; Moore, James M; Moser, Russell; Bernard, Brady; Teater, Matt; Smith, Leslie E; Rabaia, Natalia A; Gurley, Kay E; Guinney, Justin; Busch, Stephanie E; Shaknovich, Rita; Lobanenkov, Victor V; Liggitt, Denny; Shmulevich, Ilya; Melnick, Ari; Filippova, Galina N

Published In Cell Rep, (2014 May 22)

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.

PubMed ID: 24794443 Exiting the NIEHS site

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

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