Histone deacetylases are critical targets of bortezomib-induced cytotoxicity in multiple myeloma

• Published in: Blood Vol. 116; no. 3; pp. 406 - 417
• Main Authors: Kikuchi, Jiro, Wada, Taeko, Shimizu, Rumi, Izumi, Tohru, Akutsu, Miyuki, Mitsunaga, Kanae, Noborio-Hatano, Kaoru, Nobuyoshi, Masaharu, Ozawa, Keiya, Kano, Yasuhiko, Furukawa, Yusuke
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 22.07.2010; Americain Society of Hematology
• Subjects: Animals; Apoptosis - drug effects; Biological and medical sciences; Boronic Acids - administration & dosage; Boronic Acids - therapeutic use; Bortezomib; Caspase 8 - metabolism; Cell Line, Tumor; Depsipeptides - administration & dosage; Down-Regulation - drug effects; Drug Synergism; Gene Knockdown Techniques; Hematologic and hematopoietic diseases; Histone Deacetylase 1 - genetics; Histone Deacetylase Inhibitors - administration & dosage; Histone Deacetylase Inhibitors - therapeutic use; Histone Deacetylases - classification; Histone Deacetylases - genetics; Histone Deacetylases - metabolism; Humans; Immunodeficiencies. Immunoglobulinopathies; Immunoglobulinopathies; Immunopathology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; Mice; Mice, Inbred NOD; Mice, SCID; Multiple Myeloma - drug therapy; Multiple Myeloma - enzymology; Multiple Myeloma - genetics; Multiple Myeloma - pathology; Pyrazines - administration & dosage; Pyrazines - therapeutic use; RNA, Small Interfering - genetics; Sp1 Transcription Factor - metabolism; Xenograft Model Antitumor Assays; Antineoplastic agent; Immunopathology; Histone deacetylase; Bortezomib; Targeting; Hematology; Cytotoxicity; Malignant hemopathy; Myeloma; Immunoglobulinopathy; Analog; Proteasome inhibitor; Lymphoproliferative syndrome; Dipeptides; Cancer
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2009-07-235663

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-κB 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.