RRC ID 12721
Author Kikuchi J, Wada T, Shimizu R, Izumi T, Akutsu M, Mitsunaga K, Noborio-Hatano K, Nobuyoshi M, Ozawa K, Kano Y, Furukawa Y.
Title Histone deacetylases are critical targets of bortezomib-induced cytotoxicity in multiple myeloma.
Journal Blood
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.
Volume 116(3)
Pages 406-17
Published 2010-7-22
DOI 10.1182/blood-2009-07-235663
PII blood-2009-07-235663
PMID 20351311
MeSH Animals Apoptosis / drug effects 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 Histone Deacetylase 1 / genetics Histone Deacetylase Inhibitors / administration & dosage Histone Deacetylase Inhibitors / therapeutic use Histone Deacetylases / classification Histone Deacetylases / genetics Histone Deacetylases / metabolism* Humans 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
IF 16.601
Times Cited 64
DNA material CSII-CMV-MCS-IRES2-Venus (RDB04383)