Gerlo Sarah, Haegeman Guy, Vanden Berghe Wim
Laboratory of Eukaryotic Gene Expression and Signal Transduction LEGEST-University Gent 11th floor K.L. Ledeganckstraat 35 9000 GENT Belgium.
Cell Signal. 2008 Aug;20(8):1489-96. doi: 10.1016/j.cellsig.2008.04.004. Epub 2008 Apr 14.
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.
多发性骨髓瘤（MM）是一种迄今为止无法治愈的造血系统恶性肿瘤。白细胞介素-6（IL-6）作为骨髓瘤细胞的自分泌生长因子，其重要性已被广泛认可，但对于骨髓瘤细胞中IL-6表达失调的机制却知之甚少。在此，我们发现，与IL-6启动子失活的骨髓瘤细胞（L363）相比，组成性表达IL-6的骨髓瘤细胞（U266）中IL-6基因的体内染色质组织有所不同。我们观察到，U266细胞中IL-6启动子的AP-1应答元件，尤其是Sp1应答元件的核酸酶可及性增强。有趣的是，我们发现用ERK抑制剂U0126处理后，Sp1从IL-6启动子上被消除。此外，用U0126或光神霉素（一种可阻止Sp1与DNA结合的抗生素）处理U266细胞可消除组成性IL-6转录，这一观察结果支持了ERK和Sp1在调节IL-6转录中的重要性。重要的是，U0126和光神霉素对U266细胞活力的抑制作用比合成糖皮质激素药物地塞米松更强，这一发现表明，靶向Sp1转录因子可能对自分泌型骨髓瘤的治疗具有重要价值。
