TMIC-71. MBNL1: A key regulator of HIF-1α mRNA stability, hypoxia memory, and hypoxia-induced stemness in Glioblastoma

Abstract Glioblastoma (GBM) is the most aggressive primary brain tumor in adults, characterized by profound heterogeneity and a dismal prognosis. A key driver of GBM aggressiveness is the subpopulation of glioma stem cells (GSCs), which exhibit enhanced self-renewal, multipotency, and resistance to therapy. Hypoxia, a hallmark of the GBM microenvironment, is a major regulator of GSC maintenance and tumor progression. In this study, we demonstrate that the RNA-binding protein MBNL1 is a critical regulator of the hypoxic response in GBM. We show that MBNL1 directly binds to the 3’ untranslated region (3’UTR) of HIF-1α mRNA, promoting its degradation and suppressing the hypoxic transcriptional program. Loss of MBNL1 leads to increased HIF-1α mRNA stability, heightened expression of HIF-1 target genes, and enhanced stemness, proliferation, and clonogenicity of GSCs. Furthermore, MBNL1 regulates the duration of the hypoxic response, effectively limiting hypoxia memory and promoting cellular homeostasis upon reoxygenation. These findings position the MBNL1-HIF-1α axis as a promising therapeutic target for GBM, warranting further investigation to translate these discoveries into clinical applications.