Shim Kyu-Won, Xi Guifa, Farnell Barbara-Mania, Kim Dong-Seok, Tsurubuchi Takao, Tomita Tadanori, Mayanil C Shekhar
Pediatric Neurosurgery Research Lab, Developmental Biology Program, Division of Pediatric Neurosurgery, Children's Hospital of Chicago Research Center and Department of Neurosurgery, Northwestern University Feinberg School of Medicine, Chicago, IL 60614, USA.
Childs Nerv Syst. 2013 Aug;29(8):1245-51. doi: 10.1007/s00381-013-2087-7. Epub 2013 Apr 28.
This study investigated epigenetic modifications in human central nervous system atypical teratoid rhabdoid tumors (AT/RTs), in response to inhibition of insulin-like growth factor receptor 1 (IGF-1R).
Tumor tissue was obtained from two pediatric patients, tissue was dissociated, and primary cultures were established. Cultured cells were treated with picropodophyllin (PPP; 0, 1, and 2 μM for 48 h), a selective IGF-1R inhibitor. Histone acetylation and methylation patterns (H3K9ac, H3K18ac, H3K4me3, H3K27me3) and levels of histone deacetylases (HDACs; HDAC1, HDAC3, and SirT1) and histone acetyl transferases (GCN5 and p300) were examined. H3K9ac and H3K18ac decreased in response to treatment with PPP. HDAC levels showed a biphasic response, increasing with 1 μM PPP, but then decreasing with 2 μM PPP.
Inhibition of IGF-1R modified epigenetic status in AT/RT. Determining the mechanisms behind these modifications will guide the development of novel therapeutic targets for this malignant embryonal cancer.
本研究调查了人类中枢神经系统非典型畸胎样横纹肌样肿瘤（AT/RTs）中胰岛素样生长因子受体1（IGF-1R）受抑制时的表观遗传修饰情况。
从两名儿科患者获取肿瘤组织，将组织解离并建立原代培养物。用选择性IGF-1R抑制剂足叶草苦素（PPP；0、1和2 μM，处理48小时）处理培养的细胞。检测组蛋白乙酰化和甲基化模式（H3K9ac、H3K18ac、H3K4me3、H3K27me3）以及组蛋白去乙酰化酶（HDACs；HDAC1、HDAC3和SirT1）和组蛋白乙酰转移酶（GCN5和p300）的水平。PPP处理后H3K9ac和H3K18ac降低。HDAC水平呈现双相反应，1 μM PPP处理时升高，但2 μM PPP处理时降低。
IGF-1R的抑制改变了AT/RT中的表观遗传状态。确定这些修饰背后的机制将指导针对这种恶性胚胎性癌症开发新治疗靶点。
