Journal
BLOOD
Volume 115, Issue 12, Pages 2430-2440Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2009-07-232801
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Funding
- International Myeloma Foundation
- Fonds voor Wetenschappelijk Onderzoek Vlaanderen [FWO-V1]
- Belgische Federatie tegen Kanker
- Vlaamse Liga tegen Kanker-Stichting Emmanuel Van der Schueren
- Multiple Myeloma Research Foundation
- European Stem Cell Network [EUFP6 MSCNET]
- Onderzoeksraad Vrije Universiteit Brussel [GOA48, OZR-VUB]
- Swedish Cancer Society
- Swedish Research Council [FWO-V1]
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Insulin-like growth factor-1 (IGF-1) is an important growth and survival factor in multiple myeloma (MM). Here, we demonstrate that IGF-1 induces significant down-regulation of the proapoptotic BH3-only protein Bim in MM cells. Reduced Bim levels by RNA interference (RNAi) protected cells from drug-induced cell death. The IGF-1-mediated down-regulation of Bim was the result of (1) reduced transcription by activation of the Akt pathway and inactivation of the transcription factor FoxO3a, (2) increased proteasome-mediated degradation of the Bim extra-long protein by activation of the mitogen-activated protein kinase pathway, and (3) epigenetic regulation of both the Bim and the FoxO3a promoter. Treatment of cells with the histone deacetylase inhibitor LBH589 resulted in a clear up-regulation in the expression of Bim. Furthermore, the methylation inhibitor 5-aza-2'deoxycytidine (decitabine) significantly increased the effects of LBH589. On IGF-1 treatment, the Bim promoter region was found to be unmethylated, whereas chromatin immunoprecipitation analysis of the IGF-1-treated cells showed both a reduced histone H3 tail Lys9 (H3K9) acetylation and an increased H3K9 dimethylation, which contributed actively to its silencing. These data identify a new mechanism in the IGF-1-dependent survival of MM cells and emphasize the need for IGF-1-targeted drug therapy. (Blood. 2010;115:2430-2440)
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