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09:11
Assays for Validating Histone Acetyltransferase Inhibitors
Published on: August 6, 2020
Histone deacetylase inhibitors induce mitotic slippage
F E Stevens1, H Beamish, R Warrener
1Cancer Biology Program, Diamantina Institute for Cancer Research, Immunology and Metabolic Medicine, University of Queensland, Princess Alexandra Hospital, Brisbane, Queensland, Australia.
Oncogene
|September 11, 2007
Summary
Histone deacetylase inhibitors (HDACi) cause mitotic slippage by preventing chromosomal passenger proteins from accumulating at the centromere. This failure disrupts the spindle assembly checkpoint, leading to failed cytokinesis in cancer cells.
Area of Science:
- Cell Biology
- Molecular Biology
- Cancer Research
Background:
- Chromosomal passenger proteins are crucial for mitosis and cytokinesis.
- Histone deacetylase inhibitors (HDACi) are anticancer drugs that disrupt mitosis and spindle assembly checkpoint.
- The precise mechanism of HDACi-induced mitotic disruption requires further investigation.
Purpose of the Study:
- To elucidate the mechanism by which HDACi induce aberrant mitosis and mitotic slippage.
- To investigate the role of chromosomal passenger proteins in HDACi-mediated mitotic defects.
- To understand how HDACi affect spindle assembly checkpoint function.
Main Methods:
- Cell culture treated with HDAC inhibitors.
- Microscopy to observe mitotic progression and chromosome segregation.
- Western blotting to assess protein levels and localization.
- Analysis of spindle assembly checkpoint components like BubR1.
Main Results:
- HDACi treatment causes a temporary delay in prometaphase due to spindle assembly checkpoint activation.
- Chromosomes fail to congress to the metaphase plate, leading to aberrant segregation.
- Cells undergo premature exit from mitosis (mitotic slippage) and failed cytokinesis.
- HDACi treatment prevents the centromeric accumulation of chromosomal passenger proteins.
- This deficit impairs BubR1 phosphorylation and mitotic arrest maintenance.
Conclusions:
- Centromeric accumulation of chromosomal passenger proteins is essential for regulating kinetochore functions and maintaining mitotic arrest.
- Failure in centromeric accumulation of these proteins underlies HDACi-induced mitotic slippage.
- HDACi disrupt normal mitosis by compromising the spindle assembly checkpoint via impaired chromosomal passenger protein function.
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