American Association for Cancer Research
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Supplementary Materials and Methods and Supplementary Figure Legends from Loss of the Methyl-CpG–Binding Protein ZBTB4 Alters Mitotic Checkpoint, Increases Aneuploidy, and Promotes Tumorigenesis

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journal contribution
posted on 2023-03-31, 00:28 authored by Audrey Roussel-Gervais, Ikrame Naciri, Olivier Kirsh, Laetitia Kasprzyk, Guillaume Velasco, Giacomo Grillo, Pierre Dubus, Pierre-Antoine Defossez

Supplementary methods and supplementary figure legends


Ligue Nationale contre le Cancer

Fonds de recherche en santé du Québec (FRSQ), Canada

Association pour la Recherche contre le Cancer

Groupement des Entreprises Françaises dans la Lutte contre le Cancer



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.