CTCF Haploinsufficiency Destabilizes DNA Methylation and Predisposes to 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 o...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2014-05-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124714002915 |
| _version_ | 1818038183655374848 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Christopher J. Kemp |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-10T07:38:41Z |
| format | Article |
| id | doaj.art-48463119a5594710b0d33483242f11b5 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-10T07:38:41Z |
| publishDate | 2014-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-48463119a5594710b0d33483242f11b52022-12-22T01:57:22ZengElsevierCell Reports2211-12472014-05-01741020102910.1016/j.celrep.2014.04.004CTCF Haploinsufficiency Destabilizes DNA Methylation and Predisposes to CancerChristopher J. Kemp0James M. Moore1Russell Moser2Brady Bernard3Matt Teater4Leslie E. Smith5Natalia A. Rabaia6Kay E. Gurley7Justin Guinney8Stephanie E. Busch9Rita Shaknovich10Victor V. Lobanenkov11Denny Liggitt12Ilya Shmulevich13Ari Melnick14Galina N. Filippova15Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USADivision of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USADivision of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USAInstitute for Systems Biology, Seattle, WA 98106, USADivision of Hematology/Oncology, Weill Cornell Medical College, New York, NY 10021, USADivision of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USADivision of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USADivision of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USASage Bionetworks, 1100 Fairview Avenue, Seattle, WA 98109, USADivision of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USADivision of Hematology/Oncology, Weill Cornell Medical College, New York, NY 10021, USAMolecular Pathology Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, NIH, Rockville, MD 20852, USADepartment of Comparative Medicine, University of Washington, Seattle, WA 98195, USAInstitute for Systems Biology, Seattle, WA 98106, USADivision of Hematology/Oncology, Weill Cornell Medical College, New York, NY 10021, USADivision of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USAEpigenetic 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.http://www.sciencedirect.com/science/article/pii/S2211124714002915 |
| spellingShingle | 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 CTCF Haploinsufficiency Destabilizes DNA Methylation and Predisposes to Cancer Cell Reports |
| title | CTCF Haploinsufficiency Destabilizes DNA Methylation and Predisposes to Cancer |
| title_full | CTCF Haploinsufficiency Destabilizes DNA Methylation and Predisposes to Cancer |
| title_fullStr | CTCF Haploinsufficiency Destabilizes DNA Methylation and Predisposes to Cancer |
| title_full_unstemmed | CTCF Haploinsufficiency Destabilizes DNA Methylation and Predisposes to Cancer |
| title_short | CTCF Haploinsufficiency Destabilizes DNA Methylation and Predisposes to Cancer |
| title_sort | ctcf haploinsufficiency destabilizes dna methylation and predisposes to cancer |
| url | http://www.sciencedirect.com/science/article/pii/S2211124714002915 |
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