Loss of WNK2 expression by promoter gene methylation occurs in adult gliomas

Num esforço conjunto entre os grupos de investigação de Peter Jordan, do Instituto Nacional de Saúde Doutor Ricardo Jorge, e de Rui Manuel Reis, da Universidade de Minho, foi caracterizado um novo gene supressor de tumores em gliomas. Na sequência de um estudo do co-autor Joe Costello que identificou uma alta incidência de metilação do promotor do gene WNK2 em tumores do cérebro, juntou-se a expertise de Peter Jordan que tinha anteriormente clonado o gene e caracterizado a respectiva proteína cinase WNK2 com a de Rui Reis dispondo de uma grande série de tumores cerebrais, colecionado em vários hospitais nacionais e ingleses. Os resultados confirmaram que a expressão deste gene é silenciada num quinta dos casos adultos com glioma e demostrou ainda em linhas celulares que este facto resulta numa maior invasividade das células tumorais. A re-expressão do gene WNK2 nas células tumorais inibiu o seu comportamento agressivo, identificando assim um novo alvo terapêutico para esta doença.

Autores e afiliações:
Sónia Moniz, Olga Martinho, 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

Resumo:
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.

Revista:
Hum. Mol. Genet. (2013) 22 (1): 84-95.

Link:
http://hmg.oxfordjournals.org/content/22/1/84.long