Transcriptional signature of histone deacetylase inhibition in multiple myeloma: Biological and clinical implications Journal Article
| Authors: | Mitsiades, C. S.; Mitsiades, N. S.; McMullan, C. J.; Poulaki, V.; Shringarpure, R.; Hideshima, T.; Akiyama, M.; Chauhan, D.; Munshi, N.; Gu, X.; Bailey, C.; Joseph, M.; Libermann, T. A.; Richon, V. M.; Marks, P. A.; Anderson, K. C. |
| Article Title: | Transcriptional signature of histone deacetylase inhibition in multiple myeloma: Biological and clinical implications |
| 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: | signal transduction; oncoprotein; human cell; histone deacetylase inhibitor; cytotoxic agent; dna synthesis; cell survival; cell cycle; cell division; dna repair; apoptosis; bortezomib; proteasome; proteasome inhibitor; enzyme inhibition; multiple myeloma; cell growth; interleukin 6 receptor; transcription factor; dexamethasone; genetic transcription; cell differentiation; antineoplastic activity; drug effect; drug resistance; caspase inhibitor; chemosensitivity; cell line, tumor; telomerase; oncogenes; somatomedin c receptor; oncogene; tumor suppressor gene; histone; cell transformation; vorinostat; somatomedin c; polydeoxyribonucleotide synthase; phosphotransferase; histone deacetylases; enzyme assay; genes, tumor suppressor; enzyme mechanism; histone deacetylase; acetylation; apoptosis inducing factor; cell signaling; oligonucleotide microarrays; humans; human; priority journal; article; thalidomide derivative |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 101 |
| Issue: | 2 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 2004-01-13 |
| Start Page: | 540 |
| End Page: | 545 |
| Language: | English |
| DOI: | 10.1073/pnas.2536759100 |
| PROVIDER: | scopus |
| PMCID: | PMC327183 |
| PUBMED: | 14695887 |
| DOI/URL: | |
| Notes: | Proc. Natl. Acad. Sci. U. S. A. -- Cited By (since 1996):352 -- Export Date: 16 June 2014 -- CODEN: PNASA -- Source: Scopus |
