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Histone deacetylase inhibitors trigger a G2 checkpoint in normal cells that is defective in tumor cells
L Qiu1, A Burgess, D P Fairlie
1Queensland Cancer Fund Laboratories, Queensland Institute of Medical Research, and Joint Experimental Oncology Program, Department of Pathology, University of Queensland, Brisbane, Queensland, Australia.
Abstract:
Important aspects of cell cycle regulation are the checkpoints, which respond to a variety of cellular stresses to inhibit cell cycle progression and act as protective mechanisms to ensure genomic integrity. An increasing number of tumor suppressors are being demonstrated to have roles in checkpoint mechanisms, implying that checkpoint dysfunction is likely to be a common feature of cancers. Here we report that histone deacetylase inhibitors, in particular azelaic bishydroxamic acid, triggers a G2 phase cell cycle checkpoint response in normal human cells, and this checkpoint is defective in a range of tumor cell lines. Loss of this G2 checkpoint results in the tumor cells undergoing an aberrant mitosis resulting in fractured multinuclei and micronuclei and eventually cell death. This histone deacetylase inhibitor-sensitive checkpoint appears to be distinct from G2/M checkpoints activated by genotoxins and microtubule poisons and may be the human homologue of a yeast G2 checkpoint, which responds to aberrant histone acetylation states. Azelaic bishydroxamic acid may represent a new class of anticancer drugs with selective toxicity based on its ability to target a dysfunctional checkpoint mechanism in tumor cells.
Insights
Histone deacetylase inhibitors like azelaic bishydroxamic acid activate a G2 cell cycle checkpoint in normal cells, but this checkpoint is defective in tumor cells, leading to cell death. This suggests a new anticancer drug strategy targeting cancer cell vulnerabilities.
Area of Science:
- Cellular biology
- Cancer research
- Molecular oncology
Background:
- Cell cycle checkpoints are crucial for maintaining genomic integrity by halting cell division in response to stress.
- Checkpoint dysfunction is a common hallmark of cancer, contributing to uncontrolled proliferation and genomic instability.
- Tumor suppressors increasingly implicated in checkpoint mechanisms highlight the link between checkpoint failure and oncogenesis.
Purpose of the Study:
- To investigate the effect of histone deacetylase inhibitors (HDACi) on cell cycle checkpoints in normal and tumor cells.
- To determine if HDACi-induced checkpoint activation is defective in cancer.
- To explore the therapeutic potential of targeting this checkpoint defect with HDACi.
Main Methods:
- Treatment of normal human cells and various tumor cell lines with azelaic bishydroxamic acid (a specific HDACi).
- Analysis of cell cycle progression, specifically focusing on the G2 phase checkpoint.
- Assessment of mitotic fidelity, including multinucleation and micronucleation, and subsequent cell death.
- Comparison of the identified checkpoint with known G2/M checkpoints activated by genotoxins and microtubule poisons.
Main Results:
- Azelaic bishydroxamic acid induced a G2 phase cell cycle checkpoint response in normal human cells.
- This G2 checkpoint was found to be defective in a range of tested tumor cell lines.
- Tumor cells with a deficient G2 checkpoint exhibited aberrant mitosis, characterized by multinuclei and micronuclei, ultimately leading to cell death.
- The identified HDAC inhibitor-sensitive checkpoint appears distinct from other known G2/M checkpoints and may correspond to a yeast checkpoint responding to histone acetylation states.
Conclusions:
- A novel G2 cell cycle checkpoint, sensitive to histone deacetylase inhibitors, has been identified in normal human cells.
- This checkpoint is frequently defective in tumor cells, leading to mitotic errors and cell death.
- Azelaic bishydroxamic acid demonstrates selective toxicity towards tumor cells by exploiting this checkpoint deficiency, positioning it as a potential new class of anticancer therapeutics.