Diminished Condensin Gene Expression Drives Chromosome Instability That May Contribute to Colorectal Cancer Pathogenesis
Chromosome instability (CIN), or constantly evolving chromosome complements, is a form of genome instability implicated in the development and progression of many cancer types, however, the molecular determinants of CIN remain poorly understood. Condensin is a protein complex involved in chromosome...
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| Format: | Article |
| Language: | English |
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MDPI AG
2019-07-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/11/8/1066 |
| _version_ | 1797717401390809088 |
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| author | Allison K. Baergen Lucile M. Jeusset Zelda Lichtensztejn Kirk J. McManus |
| author_facet | Allison K. Baergen Lucile M. Jeusset Zelda Lichtensztejn Kirk J. McManus |
| author_sort | Allison K. Baergen |
| collection | DOAJ |
| description | Chromosome instability (CIN), or constantly evolving chromosome complements, is a form of genome instability implicated in the development and progression of many cancer types, however, the molecular determinants of CIN remain poorly understood. Condensin is a protein complex involved in chromosome compaction, and recent studies in model organisms show that aberrant compaction adversely impacts mitotic fidelity. To systematically assess the clinical and fundamental impacts that reduced condensin gene expression have in cancer, we first assessed gene copy number alterations of all eight condensin genes. Using patient derived datasets, we show that shallow/deep deletions occur frequently in 12 common cancer types. Furthermore, we show that reduced expression of each gene is associated with worse overall survival in colorectal cancer patients. To determine the overall impact that reduced condensin gene expression has on CIN, a comprehensive siRNA-based screen was performed in two karyotypically stable cell lines. Following gene silencing, quantitative imaging microscopy identified increases in CIN-associated phenotypes, including changes in nuclear areas, micronucleus formation, and chromosome numbers. Although silencing corresponded with increases in CIN phenotypes, the most pronounced phenotypes were observed following <i>SMC2</i> and <i>SMC4</i> silencing. Collectively, our clinical and fundamental findings suggest reduced condensin expression and function may be a significant, yet, underappreciated driver of colorectal cancer. |
| first_indexed | 2024-03-12T08:35:49Z |
| format | Article |
| id | doaj.art-67770600b4b74e1d96c047392330c6ca |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-12T08:35:49Z |
| publishDate | 2019-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-67770600b4b74e1d96c047392330c6ca2023-09-02T17:17:10ZengMDPI AGCancers2072-66942019-07-01118106610.3390/cancers11081066cancers11081066Diminished Condensin Gene Expression Drives Chromosome Instability That May Contribute to Colorectal Cancer PathogenesisAllison K. Baergen0Lucile M. Jeusset1Zelda Lichtensztejn2Kirk J. McManus3Department of Biochemistry & Medical Genetics, University of Manitoba, Winnipeg, MB R3E 0J9, CanadaDepartment of Biochemistry & Medical Genetics, University of Manitoba, Winnipeg, MB R3E 0J9, CanadaDepartment of Biochemistry & Medical Genetics, University of Manitoba, Winnipeg, MB R3E 0J9, CanadaDepartment of Biochemistry & Medical Genetics, University of Manitoba, Winnipeg, MB R3E 0J9, CanadaChromosome instability (CIN), or constantly evolving chromosome complements, is a form of genome instability implicated in the development and progression of many cancer types, however, the molecular determinants of CIN remain poorly understood. Condensin is a protein complex involved in chromosome compaction, and recent studies in model organisms show that aberrant compaction adversely impacts mitotic fidelity. To systematically assess the clinical and fundamental impacts that reduced condensin gene expression have in cancer, we first assessed gene copy number alterations of all eight condensin genes. Using patient derived datasets, we show that shallow/deep deletions occur frequently in 12 common cancer types. Furthermore, we show that reduced expression of each gene is associated with worse overall survival in colorectal cancer patients. To determine the overall impact that reduced condensin gene expression has on CIN, a comprehensive siRNA-based screen was performed in two karyotypically stable cell lines. Following gene silencing, quantitative imaging microscopy identified increases in CIN-associated phenotypes, including changes in nuclear areas, micronucleus formation, and chromosome numbers. Although silencing corresponded with increases in CIN phenotypes, the most pronounced phenotypes were observed following <i>SMC2</i> and <i>SMC4</i> silencing. Collectively, our clinical and fundamental findings suggest reduced condensin expression and function may be a significant, yet, underappreciated driver of colorectal cancer.https://www.mdpi.com/2072-6694/11/8/1066condensinchromosome instabilitycolorectal cancersingle cell quantitative imaging microscopymicronucleus |
| spellingShingle | Allison K. Baergen Lucile M. Jeusset Zelda Lichtensztejn Kirk J. McManus Diminished Condensin Gene Expression Drives Chromosome Instability That May Contribute to Colorectal Cancer Pathogenesis Cancers condensin chromosome instability colorectal cancer single cell quantitative imaging microscopy micronucleus |
| title | Diminished Condensin Gene Expression Drives Chromosome Instability That May Contribute to Colorectal Cancer Pathogenesis |
| title_full | Diminished Condensin Gene Expression Drives Chromosome Instability That May Contribute to Colorectal Cancer Pathogenesis |
| title_fullStr | Diminished Condensin Gene Expression Drives Chromosome Instability That May Contribute to Colorectal Cancer Pathogenesis |
| title_full_unstemmed | Diminished Condensin Gene Expression Drives Chromosome Instability That May Contribute to Colorectal Cancer Pathogenesis |
| title_short | Diminished Condensin Gene Expression Drives Chromosome Instability That May Contribute to Colorectal Cancer Pathogenesis |
| title_sort | diminished condensin gene expression drives chromosome instability that may contribute to colorectal cancer pathogenesis |
| topic | condensin chromosome instability colorectal cancer single cell quantitative imaging microscopy micronucleus |
| url | https://www.mdpi.com/2072-6694/11/8/1066 |
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