title: Loss of WNK2 expression by promoter gene methylation occurs in adult gliomas and triggers Rac1-mediated tumour cell invasiveness.
abstract: 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 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.
authors.affiliation: Department of Human Genetics, Instituto Nacional de Saúde Doutor Ricardo Jorge, Lisbon, Portugal.
authors.forename: Sónia
authors.initials: S
authors.lastname: Moniz
authors.forename: Olga
authors.initials: O
authors.lastname: Martinho
authors.forename: Filipe
authors.initials: F
authors.lastname: Pinto
authors.forename: Bárbara
authors.initials: B
authors.lastname: Sousa
authors.forename: Cláudia
authors.initials: C
authors.lastname: Loureiro
authors.forename: Maria José
authors.initials: MJ
authors.lastname: Oliveira
authors.forename: Luís Ferreira
authors.initials: LF
authors.lastname: Moita
authors.forename: Mrinalini
authors.initials: M
authors.lastname: Honavar
authors.forename: Célia
authors.initials: C
authors.lastname: Pinheiro
authors.forename: Manuel
authors.initials: M
authors.lastname: Pires
authors.forename: José Manuel
authors.initials: JM
authors.lastname: Lopes
authors.forename: Chris
authors.initials: C
authors.lastname: Jones
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Costello
authors.forename: Joana
authors.initials: J
authors.lastname: Paredes
authors.forename: Rui Manuel
authors.initials: RM
authors.lastname: Reis
authors.forename: Peter
authors.initials: P
authors.lastname: Jordan
mesh_terms: D000328:Adult; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology; D002455:Cell Division; D045744:Cell Line, Tumor; D019175:DNA Methylation; D020868:Gene Silencing; D005909:Glioblastoma / Q000235:genetics* / Q000473:pathology; D006801:Humans; D009361:Neoplasm Invasiveness / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D020830:rac1 GTP-Binding Protein / Q000502:physiology*
chemical_list: C523482:WNK2 protein, human; D017346:Protein Serine-Threonine Kinases; D020830:rac1 GTP-Binding Protein