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http://hdl.handle.net/2445/111376
Title: | Epigenetic inactivation of the putative DNA/RNA helicase SLFN11 in human cancer confers resistance to platinum drugs |
Author: | Nogales, Vanesa Reinhold, William C. Varma, Sudhir Martínez Cardús, Anna Moutinho, Cátia Moran, Sebastian Heyn, Holger Sebio, Ana Barnadas i Molins, Agustí Pommier, Yves Esteller, Manel |
Keywords: | ADN Metilació Epigènesi Medicaments antineoplàstics Cisplatí Càncer de pulmó Càncer d'ovari DNA Methylation Epigenesis Antineoplastic agents Cisplatin Lung cancer Ovarian cancer |
Issue Date: | 2016 |
Publisher: | Impact Journals |
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. |
Note: | Reproducció del document publicat a: https://doi.org/10.18632/oncotarget.6413 |
It is part of: | Oncotarget, 2016, vol. 7, num. 3, p. 3084-3097 |
URI: | http://hdl.handle.net/2445/111376 |
Related resource: | https://doi.org/10.18632/oncotarget.6413 |
ISSN: | 1949-2553 |
Appears in Collections: | Articles publicats en revistes (Ciències Fisiològiques) Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL)) Publicacions de projectes de recerca finançats per la UE |
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