Driving Neuronal Differentiation through Reversal of an ERK1/2-miR-124-SOX9 Axis Abrogates Glioblastoma Aggressiveness

Publication date: 20 August 2019Source: Cell Reports, Volume 28, Issue 8Author(s): Hanna Sabelström, Rebecca Petri, Ksenya Shchors, Rahul Jandial, Christin Schmidt, Rohit Sacheva, Selma Masic, Edith Yuan, Trenten Fenster, Michael Martinez, Supna Saxena, Theodore P. Nicolaides, Shirin Ilkhanizadeh, Mitchel S. Berger, Evan Y. Snyder, William A. Weiss, Johan Jakobsson, Anders I. PerssonSummaryIdentifying cellular programs that drive cancers to be stem-like and treatment resistant is critical to improving outcomes in patients. Here, we demonstrate that constitutive extracellular signal-regulated kinase 1/2 (ERK1/2) activation sustains a stem-like state in glioblastoma (GBM), the most common primary malignant brain tumor. Pharmacological inhibition of ERK1/2 activation restores neurogenesis during murine astrocytoma formation, inducing neuronal differentiation in tumorspheres. Constitutive ERK1/2 activation globally regulates miRNA expression in murine and human GBMs, while neuronal differentiation of GBM tumorspheres following the inhibition of ERK1/2 activation requires the functional expression of miR-124 and the depletion of its target gene SOX9. Overexpression of miR124 depletes SOX9 in vivo and promotes a stem-like-to-neuronal transition, with reduced tumorigenicity and increased radiation sensitivity. Providing a rationale for reports demonstrating miR-124-induced abrogation of GBM aggressiveness, we conclude that reversal of an ERK1/2-miR-124-SOX9 axis induces a neuronal...
Source: Cell Reports - Category: Cytology Source Type: research