Loss of the Methyl-CpG-Binding Protein ZBTB4 Alters Mitotic Checkpoint, Increases Aneuploidy, and Promotes Tumorigenesis

Chromosome segregation during mitosis is monitored by the mitotic checkpoint and is dependent upon DNA methylation. ZBTB4 is a mammalian epigenetic regulator with high affinity for methylated CpGs that localizes at pericentromeric heterochromatin and is frequently downregulated in cancer. Here, we r...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2017-01, Vol.77 (1), p.62-73
Main Authors: Roussel-Gervais, Audrey, Naciri, Ikrame, Kirsh, Olivier, Kasprzyk, Laetitia, Velasco, Guillaume, Grillo, Giacomo, Dubus, Pierre, Defossez, Pierre-Antoine
Format: Article
Language:English
Subjects:
12-O-Tetradecanoylphorbol-13-acetate
9,10-Dimethyl-1,2-benzanthracene
Acetic acid
Aneuploidy
Animals
Anthracene
Auditory defects
Blotting, Western
Cancer
Carcinogenesis
Cell Transformation, Neoplastic - genetics
Chromosomes
CpG islands
Disease Models, Animal
DNA methylation
Epigenetics
Flow Cytometry
Gene expression
Genomes
Genomic instability
Genomic Instability - genetics
Heterochromatin
Humans
In Situ Hybridization, Fluorescence
M Phase Cell Cycle Checkpoints - genetics
Mice
Mice, Knockout
Micronuclei
Microscopy, Confocal
Mitosis
Neoplasms - genetics
Oligonucleotide Array Sequence Analysis
Repressor Proteins - genetics
Skin
Skin cancer
Skin Neoplasms - genetics
Transcription
Tumorigenesis
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Summary:Chromosome segregation during mitosis is monitored by the mitotic checkpoint and is dependent upon DNA methylation. ZBTB4 is a mammalian epigenetic regulator with high affinity for methylated CpGs that localizes at pericentromeric heterochromatin and is frequently downregulated in cancer. Here, we report that decreased ZBTB4 expression correlates with high genome instability across many frequent human cancers. In human cell lines, ZBTB4 depletion was sufficient to increase the prevalence of micronuclei and binucleated cells in parallel with aberrant mitotic checkpoint gene expression, a weakened mitotic checkpoint, and an increased frequency of lagging chromosomes during mitosis. To extend these findings, we generated Zbtb4-deficient mice. Zbtb4 mice were smaller than their wild-type littermates. Primary cells isolated from Zbtb4 mice exhibited diminished mitotic checkpoint activity, increased mitotic defects, aneuploid cells marked by a specific transcriptional signature, and increased genomic instability. Zbtb4 mice were also more susceptible to 7,12-dimethylbenz(a)anthracene/12-O-tetradecanoylphorbol-13-acetate (DMBA/TPA)-induced skin carcinogenesis. Our results establish the epigenetic regulator ZBTB4 as an essential component in maintaining genomic stability in mammals. Cancer Res; 77(1); 62-73. ©2016 AACR.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.can-16-1181