Loading…
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...
Saved in:
| Published in: | Cancer research (Chicago, Ill.) Ill.), 2017-01, Vol.77 (1), p.62-73 |
|---|---|
| Main Authors: | , , , , , , , |
| Format: | Article |
| Language: | English |
| Subjects: | |
| Citations: | Items that this one cites Items that cite this one |
| Online Access: | Get full text |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| cited_by | cdi_FETCH-LOGICAL-c535t-9d04c63239f948bccc44ad91d7d51ca36146a1976545f27859a65cd6524b10c63 |
|---|---|
| cites | cdi_FETCH-LOGICAL-c535t-9d04c63239f948bccc44ad91d7d51ca36146a1976545f27859a65cd6524b10c63 |
| container_end_page | 73 |
| container_issue | 1 |
| container_start_page | 62 |
| container_title | Cancer research (Chicago, Ill.) |
| container_volume | 77 |
| creator | Roussel-Gervais, Audrey Naciri, Ikrame Kirsh, Olivier Kasprzyk, Laetitia Velasco, Guillaume Grillo, Giacomo Dubus, Pierre Defossez, Pierre-Antoine |
| description | 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. |
| doi_str_mv | 10.1158/0008-5472.can-16-1181 |
| format | article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_1868317122</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>1868317122</sourcerecordid><originalsourceid>FETCH-LOGICAL-c535t-9d04c63239f948bccc44ad91d7d51ca36146a1976545f27859a65cd6524b10c63</originalsourceid><addsrcrecordid>eNpdkUFv1DAQhS0EokvhJ4AsceHQlExiO85xN2pLpS1w2F56sby203VJ7GA7Uvff11FLD5xGI33vaeY9hD5DeQ5A-feyLHlBSVOdK-kKYAUAhzdoBbTmRUMIfYtWr8wJ-hDjQ14plPQ9OqkavnB8hR63Pkbse5wOBt-YdDgORTddFRvrtHX3-HfwyViH7za7DcHrIZkQ8Y1NPlmFu4NRfyZvXTrD104FI6OJeO3MPA3e6uMZlk4vFmM2iXg3jz7Ye-NMtPEjetfLIZpPL_MU3V5e7LofxfbX1XW33haK1jQVrS6JYnVVt31L-F4pRYjULehGU1CyZkCYhLZhlNA-v0VbyajSjFZkD2VWnqJvz75T8H9nE5MYbVRmGKQzfo4COOM1NFBVGf36H_rg5-DydQJaXleUcEoyRZ8pFXJ0wfRiCnaU4SigFEs1YoldLLGLbv1TABNLNVn35cV93o9Gv6r-dVE_ASvBiP8</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1983254854</pqid></control><display><type>article</type><title>Loss of the Methyl-CpG-Binding Protein ZBTB4 Alters Mitotic Checkpoint, Increases Aneuploidy, and Promotes Tumorigenesis</title><source>EZB Free E-Journals</source><creator>Roussel-Gervais, Audrey ; Naciri, Ikrame ; Kirsh, Olivier ; Kasprzyk, Laetitia ; Velasco, Guillaume ; Grillo, Giacomo ; Dubus, Pierre ; Defossez, Pierre-Antoine</creator><creatorcontrib>Roussel-Gervais, Audrey ; Naciri, Ikrame ; Kirsh, Olivier ; Kasprzyk, Laetitia ; Velasco, Guillaume ; Grillo, Giacomo ; Dubus, Pierre ; Defossez, Pierre-Antoine</creatorcontrib><description>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.</description><identifier>ISSN: 0008-5472</identifier><identifier>EISSN: 1538-7445</identifier><identifier>DOI: 10.1158/0008-5472.can-16-1181</identifier><identifier>PMID: 27815388</identifier><language>eng</language><publisher>United States: American Association for Cancer Research, Inc</publisher><subject>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</subject><ispartof>Cancer research (Chicago, Ill.), 2017-01, Vol.77 (1), p.62-73</ispartof><rights>2016 American Association for Cancer Research.</rights><rights>Copyright American Association for Cancer Research, Inc. Jan 1, 2017</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c535t-9d04c63239f948bccc44ad91d7d51ca36146a1976545f27859a65cd6524b10c63</citedby><cites>FETCH-LOGICAL-c535t-9d04c63239f948bccc44ad91d7d51ca36146a1976545f27859a65cd6524b10c63</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,786,790,27957,27958</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27815388$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Roussel-Gervais, Audrey</creatorcontrib><creatorcontrib>Naciri, Ikrame</creatorcontrib><creatorcontrib>Kirsh, Olivier</creatorcontrib><creatorcontrib>Kasprzyk, Laetitia</creatorcontrib><creatorcontrib>Velasco, Guillaume</creatorcontrib><creatorcontrib>Grillo, Giacomo</creatorcontrib><creatorcontrib>Dubus, Pierre</creatorcontrib><creatorcontrib>Defossez, Pierre-Antoine</creatorcontrib><title>Loss of the Methyl-CpG-Binding Protein ZBTB4 Alters Mitotic Checkpoint, Increases Aneuploidy, and Promotes Tumorigenesis</title><title>Cancer research (Chicago, Ill.)</title><addtitle>Cancer Res</addtitle><description>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.</description><subject>12-O-Tetradecanoylphorbol-13-acetate</subject><subject>9,10-Dimethyl-1,2-benzanthracene</subject><subject>Acetic acid</subject><subject>Aneuploidy</subject><subject>Animals</subject><subject>Anthracene</subject><subject>Auditory defects</subject><subject>Blotting, Western</subject><subject>Cancer</subject><subject>Carcinogenesis</subject><subject>Cell Transformation, Neoplastic - genetics</subject><subject>Chromosomes</subject><subject>CpG islands</subject><subject>Disease Models, Animal</subject><subject>DNA methylation</subject><subject>Epigenetics</subject><subject>Flow Cytometry</subject><subject>Gene expression</subject><subject>Genomes</subject><subject>Genomic instability</subject><subject>Genomic Instability - genetics</subject><subject>Heterochromatin</subject><subject>Humans</subject><subject>In Situ Hybridization, Fluorescence</subject><subject>M Phase Cell Cycle Checkpoints - genetics</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Micronuclei</subject><subject>Microscopy, Confocal</subject><subject>Mitosis</subject><subject>Neoplasms - genetics</subject><subject>Oligonucleotide Array Sequence Analysis</subject><subject>Repressor Proteins - genetics</subject><subject>Skin</subject><subject>Skin cancer</subject><subject>Skin Neoplasms - genetics</subject><subject>Transcription</subject><subject>Tumorigenesis</subject><issn>0008-5472</issn><issn>1538-7445</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><recordid>eNpdkUFv1DAQhS0EokvhJ4AsceHQlExiO85xN2pLpS1w2F56sby203VJ7GA7Uvff11FLD5xGI33vaeY9hD5DeQ5A-feyLHlBSVOdK-kKYAUAhzdoBbTmRUMIfYtWr8wJ-hDjQ14plPQ9OqkavnB8hR63Pkbse5wOBt-YdDgORTddFRvrtHX3-HfwyViH7za7DcHrIZkQ8Y1NPlmFu4NRfyZvXTrD104FI6OJeO3MPA3e6uMZlk4vFmM2iXg3jz7Ye-NMtPEjetfLIZpPL_MU3V5e7LofxfbX1XW33haK1jQVrS6JYnVVt31L-F4pRYjULehGU1CyZkCYhLZhlNA-v0VbyajSjFZkD2VWnqJvz75T8H9nE5MYbVRmGKQzfo4COOM1NFBVGf36H_rg5-DydQJaXleUcEoyRZ8pFXJ0wfRiCnaU4SigFEs1YoldLLGLbv1TABNLNVn35cV93o9Gv6r-dVE_ASvBiP8</recordid><startdate>20170101</startdate><enddate>20170101</enddate><creator>Roussel-Gervais, Audrey</creator><creator>Naciri, Ikrame</creator><creator>Kirsh, Olivier</creator><creator>Kasprzyk, Laetitia</creator><creator>Velasco, Guillaume</creator><creator>Grillo, Giacomo</creator><creator>Dubus, Pierre</creator><creator>Defossez, Pierre-Antoine</creator><general>American Association for Cancer Research, Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7T5</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>RC3</scope></search><sort><creationdate>20170101</creationdate><title>Loss of the Methyl-CpG-Binding Protein ZBTB4 Alters Mitotic Checkpoint, Increases Aneuploidy, and Promotes Tumorigenesis</title><author>Roussel-Gervais, Audrey ; Naciri, Ikrame ; Kirsh, Olivier ; Kasprzyk, Laetitia ; Velasco, Guillaume ; Grillo, Giacomo ; Dubus, Pierre ; Defossez, Pierre-Antoine</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c535t-9d04c63239f948bccc44ad91d7d51ca36146a1976545f27859a65cd6524b10c63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>12-O-Tetradecanoylphorbol-13-acetate</topic><topic>9,10-Dimethyl-1,2-benzanthracene</topic><topic>Acetic acid</topic><topic>Aneuploidy</topic><topic>Animals</topic><topic>Anthracene</topic><topic>Auditory defects</topic><topic>Blotting, Western</topic><topic>Cancer</topic><topic>Carcinogenesis</topic><topic>Cell Transformation, Neoplastic - genetics</topic><topic>Chromosomes</topic><topic>CpG islands</topic><topic>Disease Models, Animal</topic><topic>DNA methylation</topic><topic>Epigenetics</topic><topic>Flow Cytometry</topic><topic>Gene expression</topic><topic>Genomes</topic><topic>Genomic instability</topic><topic>Genomic Instability - genetics</topic><topic>Heterochromatin</topic><topic>Humans</topic><topic>In Situ Hybridization, Fluorescence</topic><topic>M Phase Cell Cycle Checkpoints - genetics</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>Micronuclei</topic><topic>Microscopy, Confocal</topic><topic>Mitosis</topic><topic>Neoplasms - genetics</topic><topic>Oligonucleotide Array Sequence Analysis</topic><topic>Repressor Proteins - genetics</topic><topic>Skin</topic><topic>Skin cancer</topic><topic>Skin Neoplasms - genetics</topic><topic>Transcription</topic><topic>Tumorigenesis</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Roussel-Gervais, Audrey</creatorcontrib><creatorcontrib>Naciri, Ikrame</creatorcontrib><creatorcontrib>Kirsh, Olivier</creatorcontrib><creatorcontrib>Kasprzyk, Laetitia</creatorcontrib><creatorcontrib>Velasco, Guillaume</creatorcontrib><creatorcontrib>Grillo, Giacomo</creatorcontrib><creatorcontrib>Dubus, Pierre</creatorcontrib><creatorcontrib>Defossez, Pierre-Antoine</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Immunology Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><jtitle>Cancer research (Chicago, Ill.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Roussel-Gervais, Audrey</au><au>Naciri, Ikrame</au><au>Kirsh, Olivier</au><au>Kasprzyk, Laetitia</au><au>Velasco, Guillaume</au><au>Grillo, Giacomo</au><au>Dubus, Pierre</au><au>Defossez, Pierre-Antoine</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Loss of the Methyl-CpG-Binding Protein ZBTB4 Alters Mitotic Checkpoint, Increases Aneuploidy, and Promotes Tumorigenesis</atitle><jtitle>Cancer research (Chicago, Ill.)</jtitle><addtitle>Cancer Res</addtitle><date>2017-01-01</date><risdate>2017</risdate><volume>77</volume><issue>1</issue><spage>62</spage><epage>73</epage><pages>62-73</pages><issn>0008-5472</issn><eissn>1538-7445</eissn><notes>ObjectType-Article-1</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-2</notes><notes>content type line 23</notes><abstract>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.</abstract><cop>United States</cop><pub>American Association for Cancer Research, Inc</pub><pmid>27815388</pmid><doi>10.1158/0008-5472.can-16-1181</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0008-5472 |
| ispartof | Cancer research (Chicago, Ill.), 2017-01, Vol.77 (1), p.62-73 |
| issn | 0008-5472 1538-7445 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_1868317122 |
| source | EZB Free E-Journals |
| 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 |
| title | Loss of the Methyl-CpG-Binding Protein ZBTB4 Alters Mitotic Checkpoint, Increases Aneuploidy, and Promotes Tumorigenesis |
| url | http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-09-21T05%3A30%3A35IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Loss%20of%20the%20Methyl-CpG-Binding%20Protein%20ZBTB4%20Alters%20Mitotic%20Checkpoint,%20Increases%20Aneuploidy,%20and%20Promotes%20Tumorigenesis&rft.jtitle=Cancer%20research%20(Chicago,%20Ill.)&rft.au=Roussel-Gervais,%20Audrey&rft.date=2017-01-01&rft.volume=77&rft.issue=1&rft.spage=62&rft.epage=73&rft.pages=62-73&rft.issn=0008-5472&rft.eissn=1538-7445&rft_id=info:doi/10.1158/0008-5472.can-16-1181&rft_dat=%3Cproquest_cross%3E1868317122%3C/proquest_cross%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-c535t-9d04c63239f948bccc44ad91d7d51ca36146a1976545f27859a65cd6524b10c63%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=1983254854&rft_id=info:pmid/27815388&rfr_iscdi=true |