Sialidase NEU4 is involved in glioblastoma stem cell renewal and survival

Glioblastoma multiforme (GBM) is the most lethal primary brain tumor. GBM progression is strictly related to the malignant behavior of a cell subpopulation that shows stem characteristics. This subpopulation is known as GBM stem cells and is endowed with a great potential of self-renewal and resistance to radio/chemotherapy. We demonstrated that GBM stem cells isolated from the cell line U87MG and from patients show a significant up-regulation of the sialidase NEU4, in comparison to GBM cells, which constitute the bulk of tumor. In order to understand the significance of the altered expression of NEU4, we stably silenced it by RNA interference in GBM stem cells isolated from the U87MG cell line. After silencing, GBM stem cell survival significantly decreased (69% after 15 days). The primary mechanism of cell death was assessed to be mitotic catastrophe, as demonstrated by the presence of multiple nuclei in single cells and by the block of cell cycle in G2/M phase with an increase of cyclin B1. A partial inhibition of key signaling pathways directly connected with GBM stem cell renewal came before cell death: in particular, we detected the increase of the active form of GSKβ3 that inhibits Sonic Hedgehog and Wnt/β catenin pathways and in parallel we recorded the decrease, as mRNA expression, of the transcriptional factors NANOG, OCT-4, SOX-2, GLI-1, β catenin. In addition, ganglioside GD3 content decreased because of Sp1 factors and GD3 synthase expression decrease. Ganglioside GD3 is severely implicated in GBM progression.1 It could be hypothesized that NEU4 could control GSKβ3 activity through the desialylation of particular glycoproteins, as previously described.2 Based on these results, NEU4 up-regulation could be considered an alteration significantly interconnected with GBM stem cell survival and could represent a novel cue for therapy. 1. Sa G et al (2009) Cancer Res. 69(7):3095-104 2. Tringali C et al (2012) Int J Cancer 131(8):1768-78