TitleCTCF haploinsufficiency destabilizes DNA methylation and predisposes to cancer.
Publication TypeJournal Article
Year of Publication2014
AuthorsKemp, 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, and Filippova Galina N.
JournalCell Rep
Date Published2014 May 22
KeywordsAnimals, 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, Protein Binding, Repressor Proteins, Survival Analysis

<p>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.</p>

Alternate JournalCell Rep
PubMed ID24794443
PubMed Central IDPMC4040130
Grant ListU24 CA143835 / CA / NCI NIH HHS / United States
DA030326 / DA / NIDA NIH HHS / United States
T32 GM007270 / GM / NIGMS NIH HHS / United States
U01 CA176303 / CA / NCI NIH HHS / United States
CA68360 / CA / NCI NIH HHS / United States
U01 CA141550 / CA / NCI NIH HHS / United States
P30 ES007033 / ES / NIEHS NIH HHS / United States
ES007033 / ES / NIEHS NIH HHS / United States
U54 CA132381 / CA / NCI NIH HHS / United States
R01 CA068360 / CA / NCI NIH HHS / United States
U24CA143835 / CA / NCI NIH HHS / United States
P30 DK056465 / DK / NIDDK NIH HHS / United States