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

CTCF haploinsufficiency destabilizes DNA methylation and predisposes to cancer.

Author information

1
Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA. Electronic address: cjkemp@fhcrc.org.
2
Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
3
Institute for Systems Biology, Seattle, WA 98106, USA.
4
Division of Hematology/Oncology, Weill Cornell Medical College, New York, NY 10021, USA.
5
Sage Bionetworks, 1100 Fairview Avenue, Seattle, WA 98109, USA.
6
Molecular Pathology Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, NIH, Rockville, MD 20852, USA.
7
Department of Comparative Medicine, University of Washington, Seattle, WA 98195, USA.
8
Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA. Electronic address: gfilippo@fhcrc.org.

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.

PMID:
24794443
PMCID:
PMC4040130
DOI:
10.1016/j.celrep.2014.04.004
[Indexed for MEDLINE]
Free PMC Article
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