p53 and miR-210 regulated NeuroD2, a neuronal basic helix-loop-helix transcription factor, is downregulated in glioblastoma patients and functions as a tumor suppressor under hypoxic microenvironment.

The factors involved in cell differentiation have recently garnered interest for their role in inhibition of pathogenesis in various tumors. However, their role in glioblastoma (GBM) remains poorly understood. We analyzed The Cancer Genome Atlas (TCGA) GBM data and found significant downregulation of neurogenic differentiation factor NeuroD2 in GBM patients. Low levels of NeuroD2 were found to be correlated with poor overall survival of GBM patients in TCGA dataset as well as in our cohort. Interestingly, NeuroD2 was shown to be transcriptionally induced by p53 and post-transcriptionally targeted by hypoxia- inducible miRNA, miR-210. NeuroD2 overexpression diminished GBM aggressiveness by inhibiting cell proliferation, migration and promoting apoptosis under hypoxia. NeuroD2 overexpressing GBM cells failed to form three-dimensional (3D)-tumor spheroids and displayed reduced migration in a 3D gelatin matrix. NeuroD2 gene signature was enriched in pathways belonging to cytokine-cytokine receptor interaction, TNF-signaling, PI3K-AKT signaling, focal adhesion and ECM-receptor interaction. Overall, our study identifies a novel role of NeuroD2 as a tumor suppressor and prognostic biomarker in GBM the levels of which are tightly regulated by p53 and miR-210. Overexpressing NeuroD2 may potentially be a simple and efficient therapeutic strategy to inhibit the malignant phenotype of GBM cells.