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Loss of WNK2 expression by promoter gene methylation occurs in adult gliomas and triggers Rac1-mediated tumour cell invasiveness

2013-01Journal article Restricted access
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dc.contributor.authorMoniz, Sónia
dc.contributor.authorMartinho, Olga
dc.contributor.authorPinto, Filipe
dc.contributor.authorSousa, Bárbara
dc.contributor.authorLoureiro, Cláudia
dc.contributor.authorOliveira, Maria José
dc.contributor.authorMoita, Luís Ferreira
dc.contributor.authorHonavar, Mrinalini
dc.contributor.authorPinheiro, Célia
dc.contributor.authorPires, Manuel
dc.contributor.authorLopes, José Manuel
dc.contributor.authorJones, Chris
dc.contributor.authorCostello, Joseph F
dc.contributor.authorParedes, Joana
dc.contributor.authorReris, Rui Manuel
dc.contributor.authorJordan, Peter
dc.date.accessioned2012-12-19T17:45:18Z
dc.date.available2012-12-19T17:45:18Z
dc.date.issued2013-01
dc.description.abstractThe gene encoding protein kinase WNK2 was recently identified to be silenced by promoter hypermethylation in gliomas and meningiomas, suggesting a tumour-suppressor role in these brain tumours. Following experimental depletion in cell lines, WNK2 was further found to control GTP-loading of Rac1, a signalling guanosine triphosphatase involved in cell migration and motility. Here we show that WNK2 promoter methylation also occurs in 17.5% (29 out of 166) of adult gliomas, whereas it is infrequent in its paediatric forms (1.6%; 1 out of 66). Re-expression of WNK2 in glioblastoma cells presenting WNK2 gene silencing reduced cell proliferation in vitro, tumour growth in vivo and also cell migration and invasion, an effect correlated with reduced activation of Rac1. In contrast, when endogenous WNK2 was depleted from glioblastoma cells with unmethylated WNK2 promoter, changes in cell morphology, an increase in invasion and activation of Rac1 were observed. Together, these results validate the WNK2 gene as a recurrent target for epigenetic silencing in glia-derived brain tumours and provide first mechanistic evidence for a tumour-suppressing role of WNK2 that is related to Rac1 signalling and tumour cell invasion and proliferation.por
dc.description.sponsorshipprojecto FCT PTDC/SAU-OBD/100079/2008por
dc.identifier.citationHum Mol Genet. 2013 Jan 1;22(1):84-95por
dc.identifier.issn0964-6906
dc.identifier.otherdoi:10.1093/hmg/dds405
dc.identifier.urihttp://hdl.handle.net/10400.18/1132
dc.language.isoengpor
dc.peerreviewedyespor
dc.publisherOxford University Presspor
dc.relation.publisherversionhttp://hmg.oxfordjournals.org/content/22/1/84.abstractpor
dc.subjectVias de Transdução de Sinal e Patologias Associadaspor
dc.subjectGliomapor
dc.subjectWNKpor
dc.subjectRac1por
dc.subjectInvasionpor
dc.subjectPromoter Methylationpor
dc.subjectEpigeneticpor
dc.titleLoss of WNK2 expression by promoter gene methylation occurs in adult gliomas and triggers Rac1-mediated tumour cell invasivenesspor
dc.typejournal article
dspace.entity.typePublication
oaire.citation.endPage95por
oaire.citation.startPage84por
oaire.citation.titleHuman Molecular Geneticspor
oaire.citation.volume22por
rcaap.rightsrestrictedAccesspor
rcaap.typearticlepor

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