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Loss of the Methyl-CpG–Binding Protein ZBTB4 Alters Mitotic Checkpoint, Increases Aneuploidy, and Promotes Tumorigenesis
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| Zeitschriftentitel: | Cancer Research |
|---|---|
| Personen und Körperschaften: | , , , , , , , |
| In: | Cancer Research, 77, 2017, 1, S. 62-73 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
American Association for Cancer Research (AACR)
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| Schlagwörter: |
| author_facet |
Roussel-Gervais, Audrey Naciri, Ikrame Kirsh, Olivier Kasprzyk, Laetitia Velasco, Guillaume Grillo, Giacomo Dubus, Pierre Defossez, Pierre-Antoine Roussel-Gervais, Audrey Naciri, Ikrame Kirsh, Olivier Kasprzyk, Laetitia Velasco, Guillaume Grillo, Giacomo Dubus, Pierre Defossez, Pierre-Antoine |
|---|---|
| author |
Roussel-Gervais, Audrey Naciri, Ikrame Kirsh, Olivier Kasprzyk, Laetitia Velasco, Guillaume Grillo, Giacomo Dubus, Pierre Defossez, Pierre-Antoine |
| spellingShingle |
Roussel-Gervais, Audrey Naciri, Ikrame Kirsh, Olivier Kasprzyk, Laetitia Velasco, Guillaume Grillo, Giacomo Dubus, Pierre Defossez, Pierre-Antoine Cancer Research Loss of the Methyl-CpG–Binding Protein ZBTB4 Alters Mitotic Checkpoint, Increases Aneuploidy, and Promotes Tumorigenesis Cancer Research Oncology |
| author_sort |
roussel-gervais, audrey |
| spelling |
Roussel-Gervais, Audrey Naciri, Ikrame Kirsh, Olivier Kasprzyk, Laetitia Velasco, Guillaume Grillo, Giacomo Dubus, Pierre Defossez, Pierre-Antoine 0008-5472 1538-7445 American Association for Cancer Research (AACR) Cancer Research Oncology http://dx.doi.org/10.1158/0008-5472.can-16-1181 <jats:title>Abstract</jats:title> <jats:p>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.</jats:p> Loss of the Methyl-CpG–Binding Protein ZBTB4 Alters Mitotic Checkpoint, Increases Aneuploidy, and Promotes Tumorigenesis Cancer Research |
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10.1158/0008-5472.can-16-1181 |
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American Association for Cancer Research (AACR), 2017 |
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American Association for Cancer Research (AACR), 2017 |
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0008-5472 1538-7445 |
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| title |
Loss of the Methyl-CpG–Binding Protein ZBTB4 Alters Mitotic Checkpoint, Increases Aneuploidy, and Promotes Tumorigenesis |
| title_unstemmed |
Loss of the Methyl-CpG–Binding Protein ZBTB4 Alters Mitotic Checkpoint, Increases Aneuploidy, and Promotes Tumorigenesis |
| title_full |
Loss of the Methyl-CpG–Binding Protein ZBTB4 Alters Mitotic Checkpoint, Increases Aneuploidy, and Promotes Tumorigenesis |
| title_fullStr |
Loss of the Methyl-CpG–Binding Protein ZBTB4 Alters Mitotic Checkpoint, Increases Aneuploidy, and Promotes Tumorigenesis |
| title_full_unstemmed |
Loss of the Methyl-CpG–Binding Protein ZBTB4 Alters Mitotic Checkpoint, Increases Aneuploidy, and Promotes Tumorigenesis |
| title_short |
Loss of the Methyl-CpG–Binding Protein ZBTB4 Alters Mitotic Checkpoint, Increases Aneuploidy, and Promotes Tumorigenesis |
| title_sort |
loss of the methyl-cpg–binding protein zbtb4 alters mitotic checkpoint, increases aneuploidy, and promotes tumorigenesis |
| topic |
Cancer Research Oncology |
| url |
http://dx.doi.org/10.1158/0008-5472.can-16-1181 |
| publishDate |
2017 |
| physical |
62-73 |
| description |
<jats:title>Abstract</jats:title>
<jats:p>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.</jats:p> |
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| author | Roussel-Gervais, Audrey, Naciri, Ikrame, Kirsh, Olivier, Kasprzyk, Laetitia, Velasco, Guillaume, Grillo, Giacomo, Dubus, Pierre, Defossez, Pierre-Antoine |
| author_facet | Roussel-Gervais, Audrey, Naciri, Ikrame, Kirsh, Olivier, Kasprzyk, Laetitia, Velasco, Guillaume, Grillo, Giacomo, Dubus, Pierre, Defossez, Pierre-Antoine, Roussel-Gervais, Audrey, Naciri, Ikrame, Kirsh, Olivier, Kasprzyk, Laetitia, Velasco, Guillaume, Grillo, Giacomo, Dubus, Pierre, Defossez, Pierre-Antoine |
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| description | <jats:title>Abstract</jats:title> <jats:p>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.</jats:p> |
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| spelling | Roussel-Gervais, Audrey Naciri, Ikrame Kirsh, Olivier Kasprzyk, Laetitia Velasco, Guillaume Grillo, Giacomo Dubus, Pierre Defossez, Pierre-Antoine 0008-5472 1538-7445 American Association for Cancer Research (AACR) Cancer Research Oncology http://dx.doi.org/10.1158/0008-5472.can-16-1181 <jats:title>Abstract</jats:title> <jats:p>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.</jats:p> Loss of the Methyl-CpG–Binding Protein ZBTB4 Alters Mitotic Checkpoint, Increases Aneuploidy, and Promotes Tumorigenesis Cancer Research |
| spellingShingle | Roussel-Gervais, Audrey, Naciri, Ikrame, Kirsh, Olivier, Kasprzyk, Laetitia, Velasco, Guillaume, Grillo, Giacomo, Dubus, Pierre, Defossez, Pierre-Antoine, Cancer Research, Loss of the Methyl-CpG–Binding Protein ZBTB4 Alters Mitotic Checkpoint, Increases Aneuploidy, and Promotes Tumorigenesis, Cancer Research, Oncology |
| title | Loss of the Methyl-CpG–Binding Protein ZBTB4 Alters Mitotic Checkpoint, Increases Aneuploidy, and Promotes Tumorigenesis |
| title_full | Loss of the Methyl-CpG–Binding Protein ZBTB4 Alters Mitotic Checkpoint, Increases Aneuploidy, and Promotes Tumorigenesis |
| title_fullStr | Loss of the Methyl-CpG–Binding Protein ZBTB4 Alters Mitotic Checkpoint, Increases Aneuploidy, and Promotes Tumorigenesis |
| title_full_unstemmed | Loss of the Methyl-CpG–Binding Protein ZBTB4 Alters Mitotic Checkpoint, Increases Aneuploidy, and Promotes Tumorigenesis |
| title_short | Loss of the Methyl-CpG–Binding Protein ZBTB4 Alters Mitotic Checkpoint, Increases Aneuploidy, and Promotes Tumorigenesis |
| title_sort | loss of the methyl-cpg–binding protein zbtb4 alters mitotic checkpoint, increases aneuploidy, and promotes tumorigenesis |
| title_unstemmed | Loss of the Methyl-CpG–Binding Protein ZBTB4 Alters Mitotic Checkpoint, Increases Aneuploidy, and Promotes Tumorigenesis |
| topic | Cancer Research, Oncology |
| url | http://dx.doi.org/10.1158/0008-5472.can-16-1181 |