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首页> 外文期刊>Molecular cancer therapeutics >Chromatin structure predicts epigenetic therapy responsiveness in sarcoma.
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Chromatin structure predicts epigenetic therapy responsiveness in sarcoma.

机译：染色质结构预测肉瘤的表观遗传治疗反应性。

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摘要

To formally explore the potential therapeutic effect of histone deacetylase inhibitors (HDACI) and DNA-methyltransferase inhibitors (DNA-MI) on sarcomas, we treated a large sarcoma cell line panel with five different HDACIs in the absence and presence of the DNA-MI decitabine. We observed that the IC(50) value of each HDACI was consistent for all cell lines whereas decitabine as a single agent showed no growth inhibition at standard doses. Combination HDACI/DNA-MI therapy showed a preferential synergism for specific sarcoma cell lines. Subsequently, we identified and validated (in vitro and in vivo) a two-gene set signature (high CUGBP2; low RHOJ) that associated with the synergistic phenotype. We further uncover that the epigenetic synergism leading to specific upregulation of CDKI p21 in specific cell lines is a function of the differences in the degree of baseline chromatin modification. Finally, we show that these chromatin and gene expression patterns are similarly present in the majority of high-grade primary sarcomas. Our results provide the first demonstration of a gene set that can predict responsiveness to HDACI/DNA-MI and links this responsiveness mechanistically to the baseline chromatin structure.
机译：为了正式探讨组蛋白脱乙酰基酶抑制剂（HDACI）和DNA-甲基转移酶抑制剂（DNA-MI）对肉瘤的潜在治疗作用，我们在不存在和存在DNA-MI地西他滨的情况下，用五种不同的HDACIs处理了一个大型肉瘤细胞系。我们观察到每个HDACI的IC（50）值在所有细胞系中均一致，而地西他滨作为单一药物在标准剂量下未显示出生长抑制作用。 HDACI / DNA-MI联合治疗对特定肉瘤细胞系显示出优先的协同作用。随后，我们鉴定并验证（体外和体内）与协同表型相关的两个基因的集合特征（高CUGBP2;低RHOJ）。我们进一步发现，导致特定细胞系中CDKI p21特异性上调的表观遗传协同作用是基线染色质修饰程度差异的函数。最后，我们表明这些染色质和基因表达模式在大多数高级原发性肉瘤中相似存在。我们的结果首次证明了可预测对HDACI / DNA-MI的反应性并将该反应性与基线染色质结构进行机械关联的基因集。

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