title: CTCF haploinsufficiency destabilizes DNA methylation and predisposes to cancer.
abstract: 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.
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA. Electronic address: cjkemp@fhcrc.org.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Kemp
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Moore
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Russell
authors.initials: R
authors.lastname: Moser
authors.affiliation: Institute for Systems Biology, Seattle, WA 98106, USA.
authors.forename: Brady
authors.initials: B
authors.lastname: Bernard
authors.affiliation: Division of Hematology/Oncology, Weill Cornell Medical College, New York, NY 10021, USA.
authors.forename: Matt
authors.initials: M
authors.lastname: Teater
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Leslie E
authors.initials: LE
authors.lastname: Smith
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Natalia A
authors.initials: NA
authors.lastname: Rabaia
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Kay E
authors.initials: KE
authors.lastname: Gurley
authors.affiliation: Sage Bionetworks, 1100 Fairview Avenue, Seattle, WA 98109, USA.
authors.forename: Justin
authors.initials: J
authors.lastname: Guinney
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Stephanie E
authors.initials: SE
authors.lastname: Busch
authors.affiliation: Division of Hematology/Oncology, Weill Cornell Medical College, New York, NY 10021, USA.
authors.forename: Rita
authors.initials: R
authors.lastname: Shaknovich
authors.affiliation: Molecular Pathology Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, NIH, Rockville, MD 20852, USA.
authors.forename: Victor V
authors.initials: VV
authors.lastname: Lobanenkov
authors.affiliation: Department of Comparative Medicine, University of Washington, Seattle, WA 98195, USA.
authors.forename: Denny
authors.initials: D
authors.lastname: Liggitt
authors.affiliation: Institute for Systems Biology, Seattle, WA 98106, USA.
authors.forename: Ilya
authors.initials: I
authors.lastname: Shmulevich
authors.affiliation: Division of Hematology/Oncology, Weill Cornell Medical College, New York, NY 10021, USA.
authors.forename: Ari
authors.initials: A
authors.lastname: Melnick
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA. Electronic address: gfilippo@fhcrc.org.
authors.forename: Galina N
authors.initials: GN
authors.lastname: Filippova
mesh_terms: D000818:Animals; D000076246:CCCTC-Binding Factor; D045744:Cell Line, Tumor; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D020022:Genetic Predisposition to Disease; D057895:Haploinsufficiency; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D016019:Survival Analysis
chemical_list: D000076246:CCCTC-Binding Factor; C000619697:CTCF protein, human; C000619698:Ctcf protein, mouse; D012097:Repressor Proteins