Transcriptional regulation of autocrine IL-6 expression in multiple myeloma cells.
Multiple myeloma (MM) is an as to date incurable hematopoietic malignancy. The importance of Interleukin-6 (IL-6) as an autocrine growth factor for MM cells is widely accepted, yet very little is known about the mechanisms at the basis of deregulated IL-6 expression in MM cells. Here we show that the in vivo chromatin organization of the IL-6 gene is different in MM cells, that constitutively express IL-6 (U266), as compared to MM cells, in which the IL-6 promoter is inactive (L363). We observed enhanced nuclease accessibility of the AP-1- and, especially, the Sp1-responsive elements in the IL-6 promoter in U266 cells. Interestingly, we found that Sp1 was eliminated from the IL-6 promoter after treatment with the ERK inhibitor U0126. The importance of ERK and Sp1 in regulating IL-6 transcription was, furthermore, supported by the observation that treatment of U266 cells with U0126 or mithramycin, an antibiotic that prevents Sp1-DNA binding, abrogated constitutive IL-6 transcription. Importantly, the finding that both U0126 and mithramycin were more potent inhibitors of U266 cell viability than the synthetic glucocorticoid drug, dexamethasone, indicates that targeting the Sp1 transcription factor might have therapeutic value in treatment of autocrine MM.
Gerlo
Sarah
S
Laboratory of Eukaryotic Gene Expression and Signal Transduction LEGEST-University Gent 11th floor K.L. Ledeganckstraat 35 9000 GENT Belgium. sarah.gerlo@ugent.be
Haegeman
Guy
G
Vanden Berghe
Wim
W
D019898:Autocrine Communication; D045744:Cell Line, Tumor; D019175:DNA Methylation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors; D015972:Gene Expression Regulation, Neoplastic; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics*; D009101:Multiple Myeloma / Q000201:enzymology / Q000235:genetics*; D011401:Promoter Regions, Genetic; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic
D056572:Histone Deacetylase Inhibitors; D015850:Interleukin-6; D047428:Protein Kinase Inhibitors; D014157:Transcription Factors; D048049:Extracellular Signal-Regulated MAP Kinases