Transcriptional signature of histone deacetylase inhibition in multiple myeloma: Biological and clinical implications
- 26 December 2003
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 101 (2), 540-545
- https://doi.org/10.1073/pnas.2536759100
Abstract
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 molecular profile of MM cells before their commitment to SAHA-induced cell death is hallmarked by 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.Keywords
This publication has 55 references indexed in Scilit:
- Identification of genes regulated by 2-methoxyestradiol (2ME2) in multiple myeloma cells using oligonucleotide arraysBlood, 2003
- Functional Characterization of the G Protein Regulator RGS13Journal of Biological Chemistry, 2002
- Intracellular regulation of tumor necrosis factor–related apoptosis-inducing ligand–induced apoptosis in human multiple myeloma cellsBlood, 2002
- Histone deacetylases and cancer: causes and therapiesNature Reviews Cancer, 2001
- Clinical Resistance to STI-571 Cancer Therapy Caused by BCR-ABL Gene Mutation or AmplificationScience, 2001
- Activity of a Specific Inhibitor of the BCR-ABL Tyrosine Kinase in the Blast Crisis of Chronic Myeloid Leukemia and Acute Lymphoblastic Leukemia with the Philadelphia ChromosomeNew England Journal of Medicine, 2001
- Gas6 Induces Growth, β-Catenin Stabilization, and T-Cell Factor Transcriptional Activation in Contact-Inhibited C57 Mammary CellsMolecular and Cellular Biology, 2001
- Apaf-1/Cytochrome c-independent and Smac-dependent Induction of Apoptosis in Multiple Myeloma (MM) CellsPublished by Elsevier BV ,2001
- The language of covalent histone modificationsNature, 2000
- Ras oncogene mutation in multiple myeloma.The Journal of Experimental Medicine, 1989