Abstract
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.
Highlights
Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in North America with approximately 170,000 new diagnoses and approximately 60,000 individuals succumbing to the disease each year [1,2]
Using HCT116, a karyotypically stable cell line, we show that reduced expression corresponds with increases in cell-to-cell heterogeneity and significant changes in key phenotypes associated with chromosome instability (CIN), including nuclear areas (NAs), micronucleus (MN) formation, and chromosome complements
Using publicly available patient derived datasets obtained from The Cancer Genome Atlas (TCGA) [23], we determined that all eight condensin genes (SMC2, SMC4, NCAPD2, NCAPD3, NCAPG, NCAPG2, NCAPH, and NCAPH2)
Summary
Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in North America with approximately 170,000 new diagnoses and approximately 60,000 individuals succumbing to the disease each year [1,2]. CRC morbidity and mortality rates requires novel insight into the aberrant genes and pathways driving disease pathogenesis. In this regard, chromosome instability (CIN) is a predominant form of genome instability found in many cancer types, but it is arguably best understood in CRC contexts. CIN is defined as an increase in the rate at which whole chromosomes, or large parts thereof, are gained or lost, and is found in up to 85% of all CRCs [3]. Two non-mutually exclusive forms of CIN exist: (1) Numerical CIN (N-CIN), which is associated with changes in chromosome numbers, and (2) Structural CIN (S-CIN), which is associated with structural changes (e.g., large deletions, insertions, and translocations) in chromosomes. Biochemical and genetics studies have revealed that CIN often arises due to defects in DNA replication, DNA repair, centrosome duplication, sister chromatid cohesion, kinetochore-microtubule attachments, mitotic spindle dynamics, and chromosome segregation, which
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
