Document Detail


Loss of WNK2 expression by promoter gene methylation occurs in adult gliomas and triggers Rac1-mediated tumour cell invasiveness.
MedLine Citation:
PMID:  23035050     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
The 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 GTPase involved in cell migration and motility. Here we show that WNK2 promoter methylation also occurs in 17.5% (29/166) of adult gliomas, whereas it is infrequent in its paediatric forms (1.6%; 1/66). 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.
Authors:
Sónia Moniz; Olga Matinho; Filipe Pinto; Bárbara Sousa; Cláudia Loureiro; Maria José Oliveira; Luís Ferreira Moita; Mrinalini Honavar; Célia Pinheiro; Manuel Pires; José Manuel Lopes; Chris Jones; Joseph F Costello; Joana Paredes; Rui Manuel Reis; Peter Jordan
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-10-3
Journal Detail:
Title:  Human molecular genetics     Volume:  -     ISSN:  1460-2083     ISO Abbreviation:  Hum. Mol. Genet.     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-10-4     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9208958     Medline TA:  Hum Mol Genet     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
Department of Human Genetics, Instituto Nacional de Saúde Doutor Ricardo Jorge, Lisbon.
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