Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Baergen, Allison K., Jeusset, Lucile M., Lichtensztejn, Zelda, McManus, Kirk J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6721357/
https://www.ncbi.nlm.nih.gov/pubmed/31357676
http://dx.doi.org/10.3390/cancers11081066
_version_ 1783448326238109696
author Baergen, Allison K.
Jeusset, Lucile M.
Lichtensztejn, Zelda
McManus, Kirk J.
author_facet Baergen, Allison K.
Jeusset, Lucile M.
Lichtensztejn, Zelda
McManus, Kirk J.
author_sort Baergen, Allison K.
collection PubMed
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 SMC2 and SMC4 silencing. Collectively, our clinical and fundamental findings suggest reduced condensin expression and function may be a significant, yet, underappreciated driver of colorectal cancer.
format Online
Article
Text
id pubmed-6721357
institution National Center for Biotechnology Information
language English
publishDate 2019
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-67213572019-09-10 Diminished Condensin Gene Expression Drives Chromosome Instability That May Contribute to Colorectal Cancer Pathogenesis Baergen, Allison K. Jeusset, Lucile M. Lichtensztejn, Zelda McManus, Kirk J. Cancers (Basel) Article 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 SMC2 and SMC4 silencing. Collectively, our clinical and fundamental findings suggest reduced condensin expression and function may be a significant, yet, underappreciated driver of colorectal cancer. MDPI 2019-07-28 /pmc/articles/PMC6721357/ /pubmed/31357676 http://dx.doi.org/10.3390/cancers11081066 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Baergen, Allison K.
Jeusset, Lucile M.
Lichtensztejn, Zelda
McManus, Kirk J.
Diminished Condensin Gene Expression Drives Chromosome Instability That May Contribute to Colorectal Cancer Pathogenesis
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 Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6721357/
https://www.ncbi.nlm.nih.gov/pubmed/31357676
http://dx.doi.org/10.3390/cancers11081066
work_keys_str_mv AT baergenallisonk diminishedcondensingeneexpressiondriveschromosomeinstabilitythatmaycontributetocolorectalcancerpathogenesis
AT jeussetlucilem diminishedcondensingeneexpressiondriveschromosomeinstabilitythatmaycontributetocolorectalcancerpathogenesis
AT lichtensztejnzelda diminishedcondensingeneexpressiondriveschromosomeinstabilitythatmaycontributetocolorectalcancerpathogenesis
AT mcmanuskirkj diminishedcondensingeneexpressiondriveschromosomeinstabilitythatmaycontributetocolorectalcancerpathogenesis