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Epigenetic Inactivation of the Putative DNA/RNA Helicase SLFN11 in Human Cancer Confers Resistance to Platinum-derived Drugs

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 to predict different sentivity to these agents in a given tumor type have been clearly identified. Because epigenetic gene silencing is increasingly being recognized as a factor in conferring distinct tumoral drug sensitivity, we have used a comprehensive DNA methylation microarray platform to interrogate the widely characterized NCI60 panel of human cancer cell lines according to CpG methylation status and cisplatin/carboplatin sensitivity. Using this approach, we have identified that promoter CpG island hypermethylation-associated silencing of the putative DNA/RNA helicase Schlafen-11 (SLFN11) is associated with increased resistance to platinum-derived compounds. We have also experimentally validated these findings in vitro. In this setting, we were also able to identify 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 were able to extend these findings to the clinical setting where we observed that those patients with ovarian and non-small cell lung cancer carrying SLFN11 hypermethylation showed poor response to cisplatin and carboplatin treatments. Overall, these results identify SLFN11 epigenetic inactivation as a predictor of resistance to platin-derived drugs in human cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE66872 | GEO | 2015/11/30

SECONDARY ACCESSION(S): PRJNA278139

REPOSITORIES: GEO

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