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HDAC Inhibitor-Induced Mitotic Arrest Is Mediated by Eg5/KIF11 Acetylation
Dhanusha A Nalawansha1, Inosha D Gomes1, Magdalene K Wambua1
1Department of Chemistry, Wayne State University, 5101 Cass Avenue, Detroit, MI 48202, USA.
Abstract:
Histone deacetylase 1 (HDAC1) is an epigenetic enzyme that regulates key cellular processes, such as cell proliferation, apoptosis, and cell survival, by deacetylating histone substrates. Aberrant expression of HDAC1 is implicated in multiple diseases, including cancer. As a consequence, HDAC inhibitors have emerged as effective anti-cancer drugs. HDAC inhibitor-induced G0/G1 cell-cycle arrest has been attributed to epigenetic transcriptional changes mediated by histone acetylation. However, the mechanism of G2/M arrest remains poorly understood. Here, we identified mitosis-related protein Eg5 (KIF11) as an HDAC1 substrate using a trapping mutant strategy. HDAC1 colocalized with Eg5 during mitosis and influenced the ATPase activity of Eg5. Importantly, an HDAC1- and HDAC2-selective inhibitor caused mitotic arrest and monopolar spindle formation, consistent with a model in which Eg5 deacetylation by HDAC1 is critical for mitotic progression. These findings revealed a previously unknown mechanism of action of HDAC inhibitors involving Eg5 acetylation, and provide a compelling mechanistic hypothesis for HDAC inhibitor-mediated G2/M arrest.
Insights
Histone deacetylase 1 (HDAC1) regulates cell processes and cancer. This study identifies Eg5 (KIF11) as an HDAC1 substrate, revealing a new mechanism for HDAC inhibitor action in cancer therapy.
Area of Science:
- Epigenetics
- Molecular Biology
- Cancer Biology
Background:
- Histone deacetylase 1 (HDAC1) is an epigenetic enzyme regulating cell proliferation, apoptosis, and survival.
- Aberrant HDAC1 expression is linked to various diseases, notably cancer, leading to the development of HDAC inhibitors as anti-cancer drugs.
- While HDAC inhibitor-induced G0/G1 cell-cycle arrest is understood via histone acetylation, the G2/M arrest mechanism remains unclear.
Purpose of the Study:
- To elucidate the mechanism behind HDAC inhibitor-induced G2/M cell-cycle arrest.
- To identify novel substrates of HDAC1 involved in mitotic progression.
Main Methods:
- Utilized a trapping mutant strategy to identify HDAC1 substrates.
- Performed co-localization studies of HDAC1 and Eg5 during mitosis.
- Assessed the impact of HDAC1 on Eg5 ATPase activity.
- Investigated the effects of an HDAC1/HDAC2-selective inhibitor on cell cycle progression and spindle formation.
Main Results:
- Identified mitosis-related protein Eg5 (KIF11) as a novel substrate of HDAC1.
- Demonstrated that HDAC1 colocalizes with Eg5 during mitosis and modulates its ATPase activity.
- Observed that an HDAC1/HDAC2-selective inhibitor induces mitotic arrest and monopolar spindle formation, indicating Eg5 deacetylation by HDAC1 is crucial for mitosis.
- These findings suggest Eg5 acetylation is a key mechanism in HDAC inhibitor-mediated G2/M arrest.
Conclusions:
- Revealed a previously unrecognized role for HDAC1 in regulating mitotic progression through deacetylation of Eg5 (KIF11).
- Established a mechanistic link between Eg5 acetylation and HDAC inhibitor-induced G2/M arrest, offering new insights into cancer therapy.
- Provides a compelling hypothesis for the action of HDAC inhibitors in cancer treatment.