Epigenetic inactivation of the putative DNA/RNA helicase SLFN11 in human cancer confers resistance to platinum drugs.
Epigenetic inactivation of the putative DNA/RNA helicase SLFN11 in human cancer confers resistance to platinum drugs.
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DOI：
10.18632/oncotarget.6413
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发表时间：
2016-01-19
期刊：
影响因子：
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通讯作者：
Esteller M
中科院分区：
文献类型：
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作者：
Nogales V;Reinhold WC;Varma S;Martinez-Cardus A;Moutinho C;Moran S;Heyn H;Sebio A;Barnadas A;Pommier Y;Esteller M
铂衍生药物如顺铂和卡铂是最常用的癌症化疗药物之一，但很少有特定的分子和细胞标志物预测这些药物在给定的肿瘤类型的差异敏感性已被明确确定。表观遗传基因沉默越来越被认为是一个因素赋予不同的肿瘤药物敏感性，所以我们使用了一个全面的DNA甲基化微阵列平台，以询问广泛表征的NCI 60面板的人类癌细胞系的CpG甲基化状态和顺铂/卡铂的敏感性。使用这种方法，我们发现启动子CpG岛高甲基化相关的沉默的推定的DNA/RNA解旋酶Schlafen-11（SLFN 11）与铂类化合物的耐药性增加。我们还在体外实验中验证了这些发现。在这种情况下，我们还确定了BRCA 1相互作用DHX 9 RNA解旋酶（也称为RHA）作为SLFN 11的蛋白质伴侣，这表明了所观察到的化学抗性效应的机制途径。最重要的是，我们已经能够在临床上扩展这些发现，观察到那些携带SLFN 11超甲基化的卵巢癌和非小细胞肺癌患者对顺铂和卡铂治疗的反应都很差。总体而言，这些结果将SLFN 11表观遗传失活鉴定为人类癌症中铂类药物耐药性的预测因子。
Platinum-derived drugs such as cisplatin and carboplatin are among the most commonly used cancer chemotherapy drugs, but very few specific molecular and cellular markers predicting differential sensitivity to these agents in a given tumor type have been clearly identified. Epigenetic gene silencing is increasingly being recognized as a factor conferring distinct tumoral drug sensitivity, so we have used a comprehensive DNA methylation microarray platform to interrogate the widely characterized NCI60 panel of human cancer cell lines with respect to CpG methylation status and cisplatin/carboplatin sensitivity. Using this approach, we have found promoter CpG island hypermethylation-associated silencing of the putative DNA/RNA helicase Schlafen-11 (SLFN11) to be associated with increased resistance to platinum compounds. We have also experimentally validated these findings in vitro. In this setting, we also identified the BRCA1 interacting DHX9 RNA helicase (also known as RHA) as a protein partner for SLFN11, suggesting a mechanistic pathway for the observed chemoresistance effect. Most importantly, we have been able to extend these findings clinically, following the observation that those patients with ovarian and non-small cell lung cancer carrying SLFN11 hypermethylation had a poor response to both cisplatin and carboplatin treatments. Overall, these results identify SLFN11 epigenetic inactivation as a predictor of resistance to platinum drugs in human cancer.