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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
Martinez-Cardús, Anna
Moutinho, Cátia
Moran, Sebastian
Heyn, Holger
Sebio, Ana
Barnadas i Molins, Agustí
Pommier, Yves
Esteller, Manel
Keywords: ADN
Medicaments antineoplàstics
Càncer de pulmó
Càncer d'ovari
Antineoplastic agents
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:
It is part of: Oncotarget, 2016, vol. 7, num. 3, p. 3084-3097
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ISSN: 1949-2553
Appears in Collections:Articles publicats en revistes (Ciències Fisiològiques)
Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))

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