Abstract
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.
Highlights
Platinum-derived compounds, such as cisplatin and its second-generation analogue carboplatin, are drugs widely used to treat human malignancies [1]
In order to identify strong candidate genes with differential methylation respect to their cisplatin or carboplatin sensitivity, we imposed stringent criteria and only considered those CpG sites harbored in CpG islands located within ± 1,500 bp of the transcription start site of the corresponding gene
These CpG sites were analyzed along the NCI60 panel by examining the Pearson’s correlation coefficients between their methylation values and the cisplatin and carboplatin IC50 values obtained from the Developmental Therapeutics Program of the NCI
Summary
Platinum-derived compounds, such as cisplatin and its second-generation analogue carboplatin, are drugs widely used to treat human malignancies [1]. The major cytotoxic mode of action of this kind of drugs is mediated by their interaction with DNA to form DNA adducts which disrupt the structure of the DNA molecule [1] This alteration of the DNA leads to the activation of DNA damage recognition and repair systems in order to allow cell cycle progression. The utility of CpG promoter island hypermethylation events as biomarkers for cancer progression or drugs response have already been demonstrated in several studies [12, 13, 14] Following this lead, and as reported here, we have adopted a nonbiased global genomic approach to identify cancer-specific epigenetic changes that could predict chemosensitivity to platinum-based compounds
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