Transcriptional signature of histone deacetylase inhibition in multiple myeloma: biological and clinical implications.
Histone deacetylases (HDACs) affect cell growth at the transcriptional level by regulating the acetylation status of nucleosomal histones. HDAC inhibition induces differentiation and/or apoptosis in transformed cells. We recently showed that HDAC inhibitors, such as suberoylanilide hydroxamic acid (SAHA), potently induce apoptosis of human multiple myeloma (MM) cells. In this study, we focused on MM as a model to study the transcriptional profile of HDAC inhibitor treatment on tumor cells and to address their pathophysiological implications with confirmatory mechanistic and functional assays. We found that MM cells are irreversibly committed to cell death within few hours of incubation with SAHA. The hallmark molecular profile of MM cells before their commitment to SAHA-induced cell death is a constellation of antiproliferative and/or proapoptotic molecular events, including down-regulation of transcripts for members of the insulin-like growth factor (IGF)/IGF-1 receptor (IGF-1R) and IL-6 receptor (IL-6R) signaling cascades, antiapoptotic molecules (e.g., caspase inhibitors), oncogenic kinases, DNA synthesis/repair enzymes, and transcription factors (e.g., XBP-1, E2F-1) implicated in MM pathophysiology. Importantly, SAHA treatment suppresses the activity of the proteasome and expression of its subunits, and enhances MM cell sensitivity to proteasome inhibition by bortezomib (PS-341). SAHA also enhances the anti-MM activity of other proapoptotic agents, including dexamethasone, cytotoxic chemotherapy, and thalidomide analogs. These findings highlight the pleiotropic antitumor effects of HDAC inhibition, and provide the framework for future clinical applications of SAHA to improve patient outcome in MM.
Mitsiades
Constantine S
CS
Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, and Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. constantine_mitsiades@dfci.harvard.edu
Mitsiades
Nicholas S
NS
McMullan
Ciaran J
CJ
Poulaki
Vassiliki
V
Shringarpure
Reshma
R
Hideshima
Teru
T
Akiyama
Masaharu
M
Chauhan
Dharminder
D
Munshi
Nikhil
N
Gu
Xuesong
X
Bailey
Charles
C
Joseph
Marie
M
Libermann
Towia A
TA
Richon
Victoria M
VM
Marks
Paul A
PA
Anderson
Kenneth C
KC
D017209:Apoptosis; D002455:Cell Division; D045744:Cell Line, Tumor; D016147:Genes, Tumor Suppressor; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D009101:Multiple Myeloma / Q000201:enzymology*; D009857:Oncogenes; D015398:Signal Transduction
D056572:Histone Deacetylase Inhibitors