Protein Pair Guides Chromosome Alignment in Mitosis

Key Points

• A joint research team from the University of Osaka and MIT discovered how two motor proteins, KIF18A and CENP-E, work together to ensure accurate chromosome congression during mitosis.
• Loss or inhibition of both proteins disrupts chromosome alignment and selectively kills cancer cells.
• Cancer cells with naturally low CENP-E levels are susceptible to KIF18A inhibitors, pointing to a potential biomarker-driven treatment strategy.

Understanding Chromosome Alignment in Cancer Cell Division

Accurate chromosome alignment during mitosis is essential for healthy cell division. When this process is disrupted, it can lead to chromosomal instability, a key characteristic observed in many cancers. A new study from The University of Osaka, conducted in collaboration with the Massachusetts Institute of Technology, uncovers a cooperative mechanism between two motor proteins, KIF18A and CENP-E, that plays a crucial role in chromosome congression. The findings not only enhance our understanding of mitotic regulation but also reveal a potential therapeutic strategy that selectively targets cancer cells.

Explore All Oncology CME/CE Conferences and Online Courses

Cooperative Function of KIF18A and CENP-E

The research team employed a genome-wide CRISPR screen in a cell model with a mild kinetochore defect resulting from a CENP-C mutation. They identified KIF18A as a key gene whose loss led to cell death when the kinetochore was already compromised. Further analysis showed that the defect included reduced activity of CENP-E, another motor protein responsible for guiding chromosome movement toward the metaphase plate.

The study demonstrated that KIF18A and CENP-E operate in tandem to ensure chromosomes align properly during the early stages of cell division. In healthy cells, if one protein functions inefficiently, the other can often compensate. However, when both are impaired, alignment fails, leading to mitotic arrest and subsequent cell death.

A Targeted Vulnerability in Cancer Cells

A notable finding was that certain cancer cells naturally display low CENP-E expression. These cells are highly sensitive to KIF18A inhibition, making them uniquely vulnerable. This suggests that measuring CENP-E levels could help identify tumors more likely to respond to KIF18A-targeting therapies. Additionally, combining inhibitors of both proteins may enhance therapeutic effectiveness against selectively vulnerable cancers.

“We not only uncovered detailed mechanisms of chromosome segregation but also applied these findings to efficiently kill cancer cells, emphasizing that such targeted therapies must be grounded in basic research.”

– Tatsuo Fukagawa, Study Senior Author and Professor, The University of Osaka

Implications for Precision Oncology

This research bridges fundamental cell biology and clinical relevance. As stated by senior author Prof. Tatsuo Fukagawa, the work highlights how basic mechanistic insight can directly inform cancer treatment strategies. For oncology professionals and clinical researchers, the study provides groundwork for biomarker-driven therapeutic development aimed at minimizing systemic toxicity while maximizing tumor specificity.

Source:

The University of Osaka