Epigenetic inactivation of the putative DNA/RNA helicase SLFN11 in human cancer confers resistance to platinum drugs
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Vanesa Nogales1, William C. Reinhold2, Sudhir Varma3, Anna Martinez-Cardus1, Catia Moutinho1, Sebastian Moran1, Holger Heyn1, Ana Sebio4, Agusti Barnadas4, Yves Pommier3, Manel Esteller1,5,6
1Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain
2Genomics and Bioinformatics Group, Developmental Therapeutics Branch, National Cancer Institute, Bethesda, MD, USA
3Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
4Department of Medical Oncology, Hospital de la Santa Ceu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Catalonia, Spain
5Department of Physiological Sciences II, School of Medicine, University of Barcelona, Barcelona, Catalonia, Spain
6Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain
Manel Esteller, e-mail: [email protected]
Keywords: SLFN11, CpG island methylation, epigenetics, chemoresistance, DNA-damaging agents
Received: August 05, 2015 Accepted: November 16, 2015 Published: November 27, 2015
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.
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