Abstract
Glioblastoma multiforme (GBM) is an aggressive brain tumor driven by cells with hallmarks of neural stem (NS) cells. GBM stem cells frequently express high levels of the transcription factors FOXG1 and SOX2. Here we show that increased expression of these factors restricts astrocyte differentiation and can trigger dedifferentiation to a proliferative NS cell state. Transcriptional targets include cell cycle and epigenetic regulators (e.g., Foxo3, Plk1, Mycn, Dnmt1, Dnmt3b, and Tet3). Foxo3 is a critical repressed downstream effector that is controlled via a conserved FOXG1/SOX2-bound cis-regulatory element. Foxo3 loss, combined with exposure to the DNA methylation inhibitor 5-azacytidine, enforces astrocyte dedifferentiation. DNA methylation profiling in differentiating astrocytes identifies changes at multiple polycomb targets, including the promoter of Foxo3 In patient-derived GBM stem cells, CRISPR/Cas9 deletion of FOXG1 does not impact proliferation in vitro; however, upon transplantation in vivo, FOXG1-null cells display increased astrocyte differentiation and up-regulate FOXO3. In contrast, SOX2 ablation attenuates proliferation, and mutant cells cannot be expanded in vitro. Thus, FOXG1 and SOX2 operate in complementary but distinct roles to fuel unconstrained self-renewal in GBM stem cells via transcriptional control of core cell cycle and epigenetic regulators.
Highlights
Glioblastoma multiforme (GBM) is a highly aggressive brain tumor driven by neural stem (NS) cell-like cells
FOXG1 protein has been shown previously to operate by attenuating the cytostatic effects of TGF-β signaling by binding and sequestration of FOXO/SMAD complexes in established glioblastoma cell lines (Seoane et al 2004)
We demonstrated that high FOXG1 and SOX2 levels, a consistent feature of GBM-derived NS (GNS) cells, are functionally important in driving a highly proliferative, growth factor-responsive, radial glia-like NS cell state
Summary
Glioblastoma multiforme (GBM) is a highly aggressive brain tumor driven by neural stem (NS) cell-like cells. FOXG1 protein has been shown previously to operate by attenuating the cytostatic effects of TGF-β signaling by binding and sequestration of FOXO/SMAD complexes in established glioblastoma cell lines (Seoane et al 2004) These findings suggest that increased levels of FOXG1 in GBM might be functionally important in driving tumor growth. Evidence in favor of this hypothesis has been provided by shRNA knockdown of FOXG1 in GBM stem cells, which leads to reduced proliferation of the resulting tumors (Verginelli et al 2013) Despite these observations, we have a poor understanding of the functional consequences of its increased levels and the downstream transcriptional targets in both NS cells and GBM stem cells. Despite the frequent expression of FOXG1/SOX2 in GBM, we have only a poor understanding of their downstream transcriptional targets and how they operate to drive proliferation and limit terminal differentiation
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