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 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.
University Paris Diderot, Sorbonne Paris Cité, Epigenetics and Cell Fate, UMR 7216 CNRS, Paris, France.
Audrey
A
Roussel-Gervais
University Paris Diderot, Sorbonne Paris Cité, Epigenetics and Cell Fate, UMR 7216 CNRS, Paris, France.
Ikrame
I
Naciri
University Paris Diderot, Sorbonne Paris Cité, Epigenetics and Cell Fate, UMR 7216 CNRS, Paris, France.
Olivier
O
Kirsh
University Paris Diderot, Sorbonne Paris Cité, Epigenetics and Cell Fate, UMR 7216 CNRS, Paris, France.
Laetitia
L
Kasprzyk
University Paris Diderot, Sorbonne Paris Cité, Epigenetics and Cell Fate, UMR 7216 CNRS, Paris, France.
Guillaume
G
Velasco
University Paris Diderot, Sorbonne Paris Cité, Epigenetics and Cell Fate, UMR 7216 CNRS, Paris, France.
Giacomo
G
Grillo
University Bordeaux, UMR INSERM 1053, Bordeaux, France.
Pierre
P
Dubus
University Paris Diderot, Sorbonne Paris Cité, Epigenetics and Cell Fate, UMR 7216 CNRS, Paris, France. pierre-antoine.defossez@univ-paris-diderot.fr.
Pierre-Antoine
PA
Defossez
D000782:Aneuploidy; D000818:Animals; D015153:Blotting, Western; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D004195:Disease Models, Animal; D005434:Flow Cytometry; D042822:Genomic Instability / Q000235:genetics*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D059566:M Phase Cell Cycle Checkpoints / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D009369:Neoplasms / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D012097:Repressor Proteins / Q000235:genetics*; D012878:Skin Neoplasms / Q000235:genetics
D012097:Repressor Proteins; C508974:ZBTB4 protein, human