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CTCF Haploinsufficiency Destabilizes DNA Methylation and Predisposes to Cancer

2014; Cell Press; Volume: 7; Issue: 4 Linguagem: Inglês

10.1016/j.celrep.2014.04.004

2639-1856

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

RNA modifications and cancer

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.