Blood Journal
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IGF-1 suppresses Bim expression in multiple myeloma via epigenetic and posttranslational mechanisms

  1. Elke De Bruyne1,*,
  2. Tomas J. Bos1,*,
  3. Frans Schuit2,
  4. Els Van Valckenborgh1,
  5. Eline Menu1,
  6. Lieven Thorrez2,
  7. Peter Atadja3,
  8. Helena Jernberg-Wiklund4, and
  9. Karin Vanderkerken1
  1. 1Department of Hematology and Immunology, Vrije Universiteit Brussel, Brussels, Belgium;
  2. 2Department of Molecular Cell Biology, Katholieke Universiteit Leuven, Leuven, Belgium;
  3. 3Novartis Institute for Biomedical Research Cambridge, Cambridge, MA; and
  4. 4Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden

Abstract

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.

  • Submitted July 28, 2009.
  • Accepted December 26, 2009.
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