title: Synergistic targeting of Sp1, a critical transcription factor for myeloma cell growth and survival, by panobinostat and proteasome inhibitors.
abstract: Panobinostat, a pan-deacetylase inhibitor, synergistically elicits cytotoxic activity against myeloma (MM) cells in combination with the proteasome inhibitor bortezomib. Because precise mechanisms for panobinostat's anti-MM action still remain elusive, we aimed to clarify the mechanisms of anti-MM effects of panobinostat and its synergism with proteasome inhibitors. Although the transcription factor Sp1 was overexpressed in MM cells, the Sp1 inhibitor terameprocol induced MM cell death in parallel with reduction of IRF4 and cMyc. Panobinostat induced activation of caspase-8, which was inversely correlated with reduction of Sp1 protein levels in MM cells. The panobinostat-mediated effects were further potentiated to effectively induce MM cell death in combination with bortezomib or carfilzomib even at suboptimal concentrations as a single agent. Addition of the caspase-8 inhibitor z-IETD-FMK abolished the Sp1 reduction not only by panobinostat alone but also by its combination with bortezomib, suggesting caspase-8-mediated Sp1 degradation. The synergistic Sp1 reduction markedly suppressed Sp1-driven prosurvival factors, IRF4 and cMyc. Besides, the combinatory treatment reduced HDAC1, another Sp1 target, in MM cells, which may potentiate HDAC inhibition. Collectively, caspase-8-mediated post-translational Sp1 degradation appears to be among major mechanisms for synergistic anti-MM effects of panobinostat and proteasome inhibitors in combination.
authors.affiliation: Department of Hematology, Endocrinology and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School of Medicine, Tokushima, Japan.
authors.forename: Ariunzaya
authors.initials: A
authors.lastname: Bat-Erdene
authors.affiliation: Division of Transfusion Medicine and Cell Therapy, Tokushima University Hospital, Tokushima, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Miki
authors.affiliation: Department of Hematology, Endocrinology and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School of Medicine, Tokushima, Japan.
authors.forename: Asuko
authors.initials: A
authors.lastname: Oda
authors.affiliation: Department of Hematology, Endocrinology and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School of Medicine, Tokushima, Japan.
authors.forename: Shingen
authors.initials: S
authors.lastname: Nakamura
authors.affiliation: Department of Hematology, Endocrinology and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School of Medicine, Tokushima, Japan.|Department of Histology and Oral Histology, Tokushima University Graduate School of Oral Sciences, Tokushima, Japan.
authors.forename: Jumpei
authors.initials: J
authors.lastname: Teramachi
authors.affiliation: Department of Hematology, Endocrinology and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School of Medicine, Tokushima, Japan.|Department of Orthodontics and Dentofacial Orthopedics, Tokushima University Graduate School of Oral Sciences, Tokushima, Japan.
authors.forename: Ryota
authors.initials: R
authors.lastname: Amachi
authors.affiliation: Department of Hematology, Endocrinology and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School of Medicine, Tokushima, Japan.|Department of Orthodontics and Dentofacial Orthopedics, Tokushima University Graduate School of Oral Sciences, Tokushima, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Tenshin
authors.affiliation: Department of Hematology, Endocrinology and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School of Medicine, Tokushima, Japan.|Department of Orthodontics and Dentofacial Orthopedics, Tokushima University Graduate School of Oral Sciences, Tokushima, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Hiasa
authors.affiliation: Department of Hematology, Endocrinology and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School of Medicine, Tokushima, Japan.
authors.forename: Masami
authors.initials: M
authors.lastname: Iwasa
authors.affiliation: Department of Hematology, Endocrinology and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School of Medicine, Tokushima, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Harada
authors.affiliation: Department of Hematology, Endocrinology and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School of Medicine, Tokushima, Japan.
authors.forename: Shiro
authors.initials: S
authors.lastname: Fujii
authors.affiliation: Department of Hematology, Endocrinology and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School of Medicine, Tokushima, Japan.
authors.forename: Kimiko
authors.initials: K
authors.lastname: Sogabe
authors.affiliation: Department of Hematology, Endocrinology and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School of Medicine, Tokushima, Japan.
authors.forename: Kumiko
authors.initials: K
authors.lastname: Kagawa
authors.affiliation: Department of Hematology, Endocrinology and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School of Medicine, Tokushima, Japan.
authors.forename: Sumiko
authors.initials: S
authors.lastname: Yoshida
authors.affiliation: Department of Hematology, Endocrinology and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School of Medicine, Tokushima, Japan.
authors.forename: Itsuro
authors.initials: I
authors.lastname: Endo
authors.affiliation: Department of Hematology, Endocrinology and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School of Medicine, Tokushima, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Aihara
authors.affiliation: Department of Hematology, Endocrinology and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School of Medicine, Tokushima, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Abe
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D000069286:Bortezomib / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D009101:Multiple Myeloma / Q000188:drug therapy / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology; D000077767:Panobinostat; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D016329:Sp1 Transcription Factor / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D006877:Hydroxamic Acids; D007211:Indoles; D009842:Oligopeptides; D061988:Proteasome Inhibitors; D016329:Sp1 Transcription Factor; C108209:SP1 protein, human; D000069286:Bortezomib; C524865:carfilzomib; D000077767:Panobinostat
keywords: Sp1; caspase-8; multiple myeloma; panobinostat; proteasome inhibitors