Discovery of the MELK–Nucleostemin Axis in Glioblastoma: Implications for p53 Regulation and Tumor Progression

Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor, classified as a World Health Organization (WHO) grade IV astrocytoma. Despite multimodal therapies, the prognosis of patients with GBM remains poor, with a median survival of only 12-16 months. The highly invasive nature and therapeutic resistance of GBM underscore the need to identify novel molecular targets. Maternal embryonic leucine zipper kinase (MELK), a serine/threonine kinase of the Snf1/AMPK family, is highly expressed in GBM and regulates cell proliferation, cell cycle progression, and stemness; however, its downstream mechanisms are unclear. Nucleostemin (NS, GNL3) is a nucleolar GTP-binding protein involved in cell proliferation and p53 regulation; however, its regulation in GBM has not been fully elucidated. In this study, we identified NS as a novel MELK substrate in glioblastoma U87MG cells. MELK directly interacts with and phosphorylates NS, promoting its proteasomal degradation. MELK overexpression decreased NS expression, leading to enhanced p53 activation and G1 cell cycle arrest. Conversely, MELK knockdown restored NS stability and attenuated p53 activation. These findings define a previously unrecognized MELK-NS-p53 signaling axis that links kinase activity to the regulation of the cell cycle. Our fundings provide mechanistic insights into glioblastoma pathogenesis and suggest that targeting the MELK-NS pathway may be a potential therapeutic strategy for high-grade gliomas.