A HIF-1a/Wnt signaling-dependent control of gene transcription regulates neuronal differentiation of glioblastoma stem cells

HIF-1a plays a crucial role in sustaining glioblastoma (GBM) cell growth and the maintenance of their undifferentiated phenotype. However, HIF-1a has been suggested to interplay with Wnt signaling components, thus activating a neuronal differentiation process in both GBM and normal brain. Here, we show that a ß-catenin/TCF1/HIF-1a complex directly controls the transcription of neuronal differentiation genes in hypoxia. Conversely, at higher oxygen levels, the increased expression of TCF4 exerts a transcriptional inhibitory function on the same genomic regions, thus counteracting differentiation. Moreover, we demonstrate the existence of a positive correlation between HIF-1a, TCF1 and neuronal phenotype in GBM tumors, accompanied by the over-expression of several Wnt signaling components, finally impacting on patient prognosis. In conclusion, we unveil a mechanism by which TCF1 and HIF-1a induce a reminiscent neuronal differentiation of hypoxic GBM cells, which is hampered, in normoxia, by high levels of TCF4, thus de facto sustaining cell aggressiveness. In this study we unveil a tightly regulated mechanism by which HIF-1a controls the balance of Wnt signaling co-factors and how their molecular interplay regulates the peculiar transcriptional events responsible for the phenotypic shift of GBM stem cells toward a reminiscent neuronal differentiation, which might represent a future potential strategy to therapeutically weaken their aggressiveness. Overall design: Gene expression was measured on Clariom S platform of cells derived from internal or periphery region of GBM tumors of 4 primary samples.