title: Histone deacetylases are critical targets of bortezomib-induced cytotoxicity in multiple myeloma.
abstract: Bortezomib is now widely used for the treatment of multiple myeloma (MM); however, its action mechanisms are not fully understood. Despite the initial results, recent investigations have indicated that bortezomib does not inactivate nuclear factor-kappaB activity in MM cells, suggesting the presence of other critical pathways leading to cytotoxicity. In this study, we show that histone deacetylases (HDACs) are critical targets of bortezomib, which specifically down-regulated the expression of class I HDACs (HDAC1, HDAC2, and HDAC3) in MM cell lines and primary MM cells at the transcriptional level, accompanied by reciprocal histone hyperacetylation. Transcriptional repression of HDACs was mediated by caspase-8-dependent degradation of Sp1 protein, the most potent transactivator of class I HDAC genes. Short-interfering RNA-mediated knockdown of HDAC1 enhanced bortezomib-induced apoptosis and histone hyperacetylation, whereas HDAC1 overexpression inhibited them. HDAC1 overexpression conferred resistance to bortezomib in MM cells, and administration of the HDAC inhibitor romidepsin restored sensitivity to bortezomib in HDAC1-overexpressing cells both in vitro and in vivo. These results suggest that bortezomib targets HDACs via distinct mechanisms from conventional HDAC inhibitors. Our findings provide a novel molecular basis and rationale for the use of bortezomib in MM treatment.
authors.affiliation: Division of Stem Cell Regulation, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan.
authors.forename: Jiro
authors.initials: J
authors.lastname: Kikuchi
authors.forename: Taeko
authors.initials: T
authors.lastname: Wada
authors.forename: Rumi
authors.initials: R
authors.lastname: Shimizu
authors.forename: Tohru
authors.initials: T
authors.lastname: Izumi
authors.forename: Miyuki
authors.initials: M
authors.lastname: Akutsu
authors.forename: Kanae
authors.initials: K
authors.lastname: Mitsunaga
authors.forename: Kaoru
authors.initials: K
authors.lastname: Noborio-Hatano
authors.forename: Masaharu
authors.initials: M
authors.lastname: Nobuyoshi
authors.forename: Keiya
authors.initials: K
authors.lastname: Ozawa
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Kano
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Furukawa
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000008:administration & dosage / Q000627:therapeutic use*; D000069286:Bortezomib; D053181:Caspase 8 / Q000378:metabolism; D045744:Cell Line, Tumor; D047630:Depsipeptides / Q000008:administration & dosage; D015536:Down-Regulation / Q000187:drug effects; D004357:Drug Synergism; D055785:Gene Knockdown Techniques; D056284:Histone Deacetylase 1 / Q000235:genetics; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use; D006655:Histone Deacetylases / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D011719:Pyrazines / Q000008:administration & dosage / Q000627:therapeutic use*; D034741:RNA, Small Interfering / Q000235:genetics; D016329:Sp1 Transcription Factor / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D001897:Boronic Acids; D047630:Depsipeptides; D056572:Histone Deacetylase Inhibitors; D011719:Pyrazines; D034741:RNA, Small Interfering; D016329:Sp1 Transcription Factor; D000069286:Bortezomib; C087123:romidepsin; C505530:CASP8 protein, human; D053181:Caspase 8; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases