Girdin Maintains the Stemness of Glioblastoma Stem Cells

Glioblastomas (GBMs) are the most common and aggressive type of brain tumor. GBMs usually show hyperactivation of the PI3K-Akt pathway, a pro-tumorigenic signaling cascade that contributes to pathogenesis. Girdin, an actin-binding protein identified as a novel substrate of Akt, regulates the sprouting of axons and the migration of neural progenitor cells during early postnatal-stage neurogenesis in the hippocampus. Here, we show that Girdin is highly expressed in human GBM. Stable Girdin knockdown in isolated GBM stem cells resulted in decreased expression of stem cell markers, including CD133, induced multilineage neural differentiation, and inhibited in vitro cell motility, ex vivo invasion, sphere-forming capacity, and in vivo tumor formation. Furthermore, exogenous expression of the Akt-binding domain of Girdin, which competitively inhibits its Akt-mediated phosphorylation, diminished the expression of stem cell markers SOX2 and nestin and migration on the brain slice, and induced the expression of neural differentiation markers GFAP/III Tubulin. Our results reveal that Girdin is required for GBM-initiating stem cells to sustain the stemness and invasive properties.

Publications

Kishida Y, Natsume A, Kondo Y, Takeuchi I, An B, Okamoto Y, Shinjo K, Saito K, Ando h, Ohka F, Sekido Y, Wakabayashi T. Epigenetic subclassification of meningiomas based on genome-wide DNA methylation analyses. Carcinogenesis, in press.
Natsume A, Kato T, Enomoto A, Kinjo S, and Wakabayashi T. (2011) Girdin maintains the stemness of glioblastoma stem cells. Oncogene, in press.
Ohka, F., Natsume, A., Motomura, K., Kishida, Y., Kondo, Y., Abe, T., Nakasu, Y., Namba, H., Wakai, K., Fukui, T. Wakabayashi T. (2011). The global DNA methylation surrogate LINE-1 methylation is correlated with MGMT promoter methylation and is a better prognostic factor for glioma. PLoS One 6, e23332.
Iwami, K., Natsume, A., and Wakabayashi, T. (2011). Cytokine networks in glioma. Neurosurgical Review 34, 253-263; discussion 263-254.