Sox2-dependent maintenance of mouse oligodendroglioma involves the Sox2-mediated downregulation of Cdkn2b, Ebf1, Zfp423 and Hey2

Abstract

Cancer stem cells (CSC) are essential for tumorigenesis. The transcription factor Sox2 is overexpressed in brain tumors. In gliomas, Sox2 is essential to maintain CSC. In mouse high-grade glioma pHGG, Sox2 deletion causes cell proliferation arrest and inability to reform tumors in vivo;134 genes are significantly derepressed. To identify genes mediating the effects of Sox2 deletion, we overexpressed into pHGG cells nine among the most derepressed genes, and identified four genes, Cdkn2b, Ebf1, Zfp423 and Hey2, that strongly reduced cell proliferation in vitro and brain tumorigenesis in vivo. CRISPR/Cas9 mutagenesis, or pharmacological inactivation, of each of these genes, individually, showed that their activity is essential for the proliferation arrest caused by Sox2 deletion. These Sox2-inhibited antioncogenes also inhibited clonogenicity in primary human glioblastoma-derived cancer stem-like cell lines. These experiments identify critical anti-oncogenic factors whose inhibition by Sox2 is involved in CSC maintenance, defining new potential therapeutic targets for gliomas. Main PointsSox2 maintains glioma tumorigenicity by repressing the antioncogenic activity of a regulatory network involving the Ebf1, Hey2, Cdkn2b and Zfp423 genes.Mutation of these genes prevents the cell proliferation arrest of Sox2-deleted glioma cells.

Specific knockout of Sox2 in astrocytes reduces reactive astrocyte formation and promotes recovery after early postnatal traumatic brain injury in mouse cortex

“…Thus, reducing astrogliosis through cell cycle inhibition improves axonal regeneration and functional recovery after TBI (Di Giovanni et al, 2005; Zhai et al, 2022). Of note, Sox2 controls the proliferation/self‐renewal of stem cells and glial cells under both normal physiological and pathological conditions through its target genes regulatory network (Barone et al, 2021; Mercurio, Serra, & Nicolis, 2019; Zhang, Zhu, et al, 2018). Consistent with the role of Sox2 in inhibiting the proliferation of reactive astrocytes and astrocytic‐scar formation after cortical injury in the adult mouse brain (Chen et al, 2019), our results demonstrated that Sox2 deficiency in astrocytes promotes neuronal regeneration and tissue recovery after cortical injury during the early postnatal period.…”

Oncogenic and Tumor-Suppressive Functions of NOTCH Signaling in Glioma

“…More direct evidence that NOTCH signaling could restrict glioma formation in some contexts comes from studies taking advantage of genetic conditional gene deletion or overexpression approaches in vivo. NOTCH2 overexpression can inhibit glioma formation in mouse glioma models [ 107 ] and HEY2 overexpression can reduce the proliferation of murine and human glioma cells [ 147 ]. Conversely, ID2-mediated repression of HEY1 promotes NSC transformation, possibly by releasing the expression of OLIG2 [ 148 ], an oligodendroglial lineage determinant involved in glioma cell proliferation [ 149 ].…”

A Composite Bioinformatic Analysis to Explore Endoplasmic Reticulum Stress-Related Prognostic Marker and Potential Pathogenic Mechanisms in Glioma by Integrating Multiomics Data

“…HEY2, one of the most prominent Notch pathway target genes, encodes a transcription factor [71]. Halani et al proposed that the loss of the Notch pathway activity and particularly of Hey2 levels were correlated with oligodendroglioma [72].…”