CTCF Haploinsufficiency Destabilizes DNA Methylation and Predisposes to Cancer
2014
Christopher J. Kemp | James M. Moore | Russell Moser | Brady Bernard | Matt Teater | Leslie E. Smith | Natalia A. Rabaia | Kay E. Gurley | Justin Guinney | Stephanie E. Busch | Rita Shaknovich | Victor V. Lobanenkov | Denny Liggitt | Ilya Shmulevich | Ari Melnick | Galina N. Filippova
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.
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