CTCF Haploinsufficiency Destabilizes DNA Methylation and Predisposes to Cancer
| Autor: | Denny Liggitt, Kay E. Gurley, James M. Moore, Russell Moser, Galina N. Filippova, Victor V. Lobanenkov, Leslie E. Smith, Stephanie E. Busch, Brady Bernard, Natalia A. Rabaia, Ari Melnick, Justin Guinney, Ilya Shmulevich, Christopher J. Kemp, Rita Shaknovich, Matt Teater |
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| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
CCCTC-Binding Factor
Mice Transgenic Haploinsufficiency Biology medicine.disease_cause General Biochemistry Genetics and Molecular Biology Article Epigenesis Genetic 03 medical and health sciences Mice 0302 clinical medicine Cell Line Tumor Neoplasms medicine Animals Humans Genes Tumor Suppressor Genetic Predisposition to Disease Epigenetics lcsh:QH301-705.5 030304 developmental biology Regulation of gene expression 0303 health sciences Mutation Cancer DNA Methylation medicine.disease Survival Analysis 3. Good health Chromatin Gene Expression Regulation Neoplastic Mice Inbred C57BL Repressor Proteins lcsh:Biology (General) CTCF 030220 oncology & carcinogenesis DNA methylation Cancer research Protein Binding |
| Zdroj: | Cell Reports, Vol 7, Iss 4, Pp 1020-1029 (2014) |
| ISSN: | 2211-1247 |
| Popis: | SummaryEpigenetic 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. |
| Databáze: | OpenAIRE |
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