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Pàgina inicial > Articles > Articles publicats > Epigenetic inactivation of the putative DNA/RNA helicase SLFN11 in human cancer confers resistance to platinum drugs |
Data: | 2015 |
Resum: | 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. |
Ajuts: | Instituto de Salud Carlos III PIE13-00022 Instituto de Salud Carlos III RTICC/RD12/0036/0039 Ministerio de Economía y Competitividad SAF2010-14935 Ministerio de Economía y Competitividad 13FIS037 Ministerio de Economía y Competitividad PT13-0001-0033 Agència de Gestió d'Ajuts Universitaris i de Recerca 2009SGR1315 Agència de Gestió d'Ajuts Universitaris i de Recerca 2014SGR633 European Commission 258677 |
Drets: | Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original. |
Llengua: | Anglès |
Document: | Article ; recerca ; Versió publicada |
Matèria: | SLFN11 ; CpG island methylation ; Epigenetics ; Chemoresistance ; DNA-damaging agents |
Publicat a: | Oncotarget, Vol. 7 (november 2015) , p. 3084-3097, ISSN 1949-2553 |
14 p, 4.9 MB |