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IGF-1 suppresses Bim expression in multiple myeloma via epigenetic and posttranslational mechanisms
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2010 (Engelska)Ingår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 115, nr 12, s. 2430-2440Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

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.

Ort, förlag, år, upplaga, sidor
2010. Vol. 115, nr 12, s. 2430-2440
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
URN: urn:nbn:se:uu:diva-133209DOI: 10.1182/blood-2009-07-232801ISI: 000275981900017PubMedID: 20086250OAI: oai:DiVA.org:uu-133209DiVA, id: diva2:360369
Tillgänglig från: 2010-11-03 Skapad: 2010-11-03 Senast uppdaterad: 2017-12-12Bibliografiskt granskad

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Jernberg-Wiklund, Helena

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