Principal Scientist, Florida Hospital Cancer Institute, Clinical Assistant Professor, Florida State University, 2501 N. Orange Ave., Suite 800, Orlando, FL 32804, USA.
Med Chem. 2011 Sep;7(5):473-9.
Aberrant methylation of tumor suppressor genes (TSG) is an important epigenetic event in cancer, including multiple myeloma (MM). Interleukin-6 (IL-6), which plays a significant role in the pathogenesis of MM, also regulates DNA methylation. However, attempts to bring IL-6 blockade to the clinic have had limited success. We hypothesize that IL-6 regulation of hypermethylation may be an important pathway leading to rational chemotherapeutic/anti-IL-6 combinations. We first studied the correlation of IL-6 expression and dependence in MM cell lines: U266B1, RPMI8226, and KAS6/1. We confirmed that KAS6/1 is IL-6-dependent whereas U266B1 and RPMI8226 cells are IL-6-independent and that blocking IL-6 inhibited the growth of U266B1 (36% inhibition; p<0.05) and KAS6/1 (68% inhibition; p<0.01), but not the RPMI8226 cells. Using RT-PCR, we showed that U266B1 cells express IL-6, but RPMI8226 and KAS6/1 cells do not. This IL-6 expression pattern correlates with the anti-IL-6 inhibition findings. To correlate IL-6 sensitivity with hypermethylation of TSG, we investigated promoter methylation of CDH1 and DcR1. We found that the promoter of DcR1 and CDH1 is methylated in U266B1 cells and un-methylated in RPMI8226 cells. Furthermore, the DcR1 promoter was un-methylated in KAS6/1 cells. These data support our hypothesis that an IL-6-dependent pathway may regulate hypermethylation of TSG in MM. Newer chemotherapeutic agents that affect methylation are being studied in combination with IL-6 blockade.
肿瘤抑制基因（TSG）的异常甲基化是癌症中的一个重要表观遗传事件，包括多发性骨髓瘤（MM）。白细胞介素 6（IL-6）在 MM 的发病机制中起重要作用，也调节 DNA 甲基化。然而，将 IL-6 阻断应用于临床的尝试收效甚微。我们假设 IL-6 对高甲基化的调节可能是导致合理化疗/抗 IL-6 联合治疗的重要途径。我们首先研究了 MM 细胞系 U266B1、RPMI8226 和 KAS6/1 中 IL-6 表达和依赖性的相关性。我们证实 KAS6/1 依赖于 IL-6，而 U266B1 和 RPMI8226 细胞不依赖于 IL-6，阻断 IL-6 抑制了 U266B1（36%抑制；p<0.05）和 KAS6/1（68%抑制；p<0.01）的生长，但不抑制 RPMI8226 细胞。通过 RT-PCR，我们表明 U266B1 细胞表达 IL-6，但 RPMI8226 和 KAS6/1 细胞不表达。这种 IL-6 表达模式与抗 IL-6 抑制的发现相关。为了将 IL-6 敏感性与 TSG 的高甲基化相关联，我们研究了 CDH1 和 DcR1 的启动子甲基化。我们发现，DcR1 和 CDH1 的启动子在 U266B1 细胞中被甲基化，而在 RPMI8226 细胞中未被甲基化。此外，DcR1 启动子在 KAS6/1 细胞中未被甲基化。这些数据支持我们的假设，即依赖于 IL-6 的途径可能调节 MM 中 TSG 的高甲基化。正在研究影响甲基化的新型化疗药物与 IL-6 阻断联合使用。
