N-terminus-modified Hec1 suppresses tumour growth by interfering with kinetochore–microtubule dynamics
Abstract
Mitotic proteins are attractive targets to develop molecular cancer therapeutics due to the intimate interdependence between cell proliferation and mitosis. In this work, we have explored the therapeutic potential of the kinetochore (KT) protein Hec1 (Highly Expressed in Cancer protein 1) as a molecular target to produce massive chromosome missegregation and cell death in cancer cells. Hec1 is a constituent of the Ndc80 complex, which mediates KT-microtubule (MT) attachments at mitosis and is upregulated in various cancer types. We expressed Hec1 fused with enhanced green fluorescent protein (EGFP) at its N-terminus MT-interaction domain in HeLa cells and showed that expression of this modified Hec1, which localized at KTs, blocked cell proliferation and promoted apoptosis in tumour cells. EGFP-Hec1 was extremely potent in tumour cell killing and more efficient than siRNA-induced Hec1 depletion. In striking contrast, normal cells showed no apparent cell proliferation defects or cell death following EGFP-Hec1 expression. Live-cell imaging demonstrated that cancer cell death was associated with massive chromosome missegregation within multipolar spindles after a prolonged mitotic arrest. Moreover, EGFP-Hec1 expression was found to increase KT-MT attachment stability, providing a molecular explanation for the abnormal spindle architecture and the cytotoxic activity of this modified protein. Consistent with cell culture data, EGFP-Hec1 expression was found to strongly inhibit tumour growth in a mouse xenograft model by disrupting mitosis and inducing multipolar spindles. Taken together, these findings demonstrate that stimulation of massive chromosome segregation defects can be used as an anti-cancer strategy through the activation of mitotic catastrophe after a multipolar mitosis. Importantly, this study represents a clear proof of concept that targeting KT proteins required for proper KT-MT attachment dynamics constitutes a powerful approach in cancer therapy.
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Chromosome missegregation can also be an inhibitor of tumorigenesis.
“However, there is now an expanding body of evidence suggesting that chromosome missegregation can also be an inhibitor of tumorigenesis56585960.”
From Mitotic Spindle Disruption by Alternating Electric Fields Leads to Improper Chromosome Segregation and Mitotic Catastrophe in Cancer Cells (2015) · cites this paper as [58]
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- Authors
- Orticello, M., Fiore, M., Totta, P., Desideri, M., Barisic, M., Passeri, D., Lenzi, J., Rosa, A., Orlandi, A., Maiato, H., Bufalo, D. D., & Degrassi, F.
- Affiliations
- National Research Council (IT)
- Instituto Nazionale Tumori Regina Elena (IT)
- University of Rome Tor Vergata (IT)
- Sapienza University of Rome (IT)
- Universidade do Porto (PT)
- Corresponding author
- Degrassi, F
- Venue
- Oncogene
- Published
- 2014-08-18
- Volume
- 34
- Issue
- 25
- Pages
- 3325-3335
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- OpenAlex
- W2023771562
- Cited by
- 12
- References
- 58
- Citations by year
- 2024: 1 · 2021: 1 · 2020: 1 · 2018: 1 · 2017: 3 · 2016: 1 · 2015: 4
- FWCI
- 1.33
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Oncogene (publishedVersion)
- PubMed (publishedVersion)
- Cineca Institutional Research Information System (Tor Vergata University) (submittedVersion)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
- Funders
- Centre National de la Recherche Scientifique
- Associazione Italiana per la Ricerca sul Cancro
- Fundação para a Ciência e a Tecnologia
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Physical Sciences › Chemistry › Organic Chemistry › Synthesis and biological activity
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- HEC-1, Ndc80 complex, kinetochore-microtubule attachment, chromosome missegregation, multipolar mitosis, mitotic catastrophe, N-terminal modification, EGFP fusion protein, tumor growth inhibition, apoptosis, mitotic arrest, cancer therapeutics
- MeSH terms
- Animals, Cell Transformation, Neoplastic, Cytoskeletal Proteins, HeLa Cells, Humans, Male, Microtubules, Mitosis, Nuclear Proteins, Recombinant Fusion Proteins, Apoptosis, Kinetochores, Tumor Suppressor Proteins, Cell Proliferation, Mice, Spindle Poles
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