Histone deacetylases are critical targets of bortezomib-induced cytotoxicity in multiple myeloma.
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.
Kikuchi
Jiro
J
Division of Stem Cell Regulation, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan.
Wada
Taeko
T
Shimizu
Rumi
R
Izumi
Tohru
T
Akutsu
Miyuki
M
Mitsunaga
Kanae
K
Noborio-Hatano
Kaoru
K
Nobuyoshi
Masaharu
M
Ozawa
Keiya
K
Kano
Yasuhiko
Y
Furukawa
Yusuke
Y
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
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