title: HDAC Inhibitor-Induced Mitotic Arrest Is Mediated by Eg5/KIF11 Acetylation.
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/G1cell-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.
authors.affiliation: Department of Chemistry, Wayne State University, 5101 Cass Avenue, Detroit, MI 48202, USA.
authors.forename: Dhanusha A
authors.initials: DA
authors.lastname: Nalawansha
authors.affiliation: Department of Chemistry, Wayne State University, 5101 Cass Avenue, Detroit, MI 48202, USA.
authors.forename: Inosha D
authors.initials: ID
authors.lastname: Gomes
authors.affiliation: Department of Chemistry, Wayne State University, 5101 Cass Avenue, Detroit, MI 48202, USA.
authors.forename: Magdalene K
authors.initials: MK
authors.lastname: Wambua
authors.affiliation: Department of Chemistry, Wayne State University, 5101 Cass Avenue, Detroit, MI 48202, USA. Electronic address: pflum@wayne.edu.
authors.forename: Mary Kay H
authors.initials: MKH
authors.lastname: Pflum
mesh_terms: D000107:Acetylation / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D057809:HEK293 Cells; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D056464:Histone Deacetylase 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D047468:Immunoprecipitation; D019169:Jurkat Cells; D016547:Kinesins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D008856:Microscopy, Fluorescence; D008938:Mitosis / Q000187:drug effects*; D016297:Mutagenesis, Site-Directed; D011485:Protein Binding; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000302:isolation & purification; D013379:Substrate Specificity; D053719:Tandem Mass Spectrometry
chemical_list: D056572:Histone Deacetylase Inhibitors; C470243:KIF11 protein, human; D011994:Recombinant Proteins; C110550:HDAC1 protein, human; C533423:HDAC2 protein, human; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D016547:Kinesins
keywords: Eg5/KIF11; HDAC inhibitor; HDAC1; histone deacetylase; substrate trapping