title: Histone deacetylase inhibitors promote glioma cell death by G2 checkpoint abrogation leading to mitotic catastrophe.
abstract: Glioblastoma multiforme is resistant to conventional anti-tumoral treatments due to its infiltrative nature and capability of relapse; therefore, research efforts focus on characterizing gliomagenesis and identifying molecular targets useful on therapy. New therapeutic strategies are being tested in patients, such as Histone deacetylase inhibitors (HDACi) either alone or in combination with other therapies. Here two HDACi included in clinical trials have been tested, suberanilohydroxamic acid (SAHA) and valproic acid (VPA), to characterize their effects on glioma cell growth in vitro and to determine the molecular changes that promote cancer cell death. We found that both HDACi reduce glioma cell viability, proliferation and clonogenicity. They have multiple effects, such as inducing the production of reactive oxygen species (ROS) and activating the mitochondrial apoptotic pathway, nevertheless cell death is not prevented by the pan-caspase inhibitor Q-VD-OPh. Importantly, we found that HDACi alter cell cycle progression by decreasing the expression of G2 checkpoint kinases Wee1 and checkpoint kinase 1 (Chk1). In addition, HDACi reduce the expression of proteins involved in DNA repair (Rad51), mitotic spindle formation (TPX2) and chromosome segregation (Survivin) in glioma cells and in human glioblastoma multiforme primary cultures. Therefore, HDACi treatment causes glioma cell entry into mitosis before DNA damage could be repaired and to the formation of an aberrant mitotic spindle that results in glioma cell death through mitotic catastrophe-induced apoptosis.
authors.affiliation: Cell Signaling and Apoptosis Group, Institut de Recerca Biomèdica de Lleida (IRBLleida), Universitat de Lleida, Lleida, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Cornago
authors.affiliation: Cell Signaling and Apoptosis Group, Institut de Recerca Biomèdica de Lleida (IRBLleida), Universitat de Lleida, Lleida, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Garcia-Alberich
authors.affiliation: Cell Signaling and Apoptosis Group, Institut de Recerca Biomèdica de Lleida (IRBLleida), Universitat de Lleida, Lleida, Spain.
authors.forename: N
authors.initials: N
authors.lastname: Blasco-Angulo
authors.affiliation: Cell Signaling and Apoptosis Group, Institut de Recerca Biomèdica de Lleida (IRBLleida), Universitat de Lleida, Lleida, Spain.
authors.forename: N
authors.initials: N
authors.lastname: Vall-Llaura
authors.affiliation: Calcium Signaling and Neuronal Differentiation Group, IRBLleida, Universitat de Lleida, Lleida, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Nager
authors.affiliation: Calcium Signaling and Neuronal Differentiation Group, IRBLleida, Universitat de Lleida, Lleida, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Herreros
authors.affiliation: Institut de Recerca de l'Hospital Universitari de la Vall d'Hebron (VHIR), Institut de Neurociències, Universitat Autònoma de Barcelona and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain.
authors.forename: J X
authors.initials: JX
authors.lastname: Comella
authors.affiliation: Cell Signaling and Apoptosis Group, Institut de Recerca Biomèdica de Lleida (IRBLleida), Universitat de Lleida, Lleida, Spain.
authors.forename: D
authors.initials: D
authors.lastname: Sanchis
authors.affiliation: Cell Signaling and Apoptosis Group, Institut de Recerca Biomèdica de Lleida (IRBLleida), Universitat de Lleida, Lleida, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Llovera
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D000071877:Checkpoint Kinase 1; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects*; D005910:Glioma / Q000188:drug therapy / Q000503:physiopathology*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D008938:Mitosis / Q000187:drug effects*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D051135:Rad51 Recombinase / Q000235:genetics / Q000378:metabolism; D014635:Valproic Acid / Q000494:pharmacology*; D000077337:Vorinostat
chemical_list: D018797:Cell Cycle Proteins; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D008869:Microtubule-Associated Proteins; D009687:Nuclear Proteins; C122167:TPX2 protein, human; D000077337:Vorinostat; D014635:Valproic Acid; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; D051135:Rad51 Recombinase