A Positive Feed-forward Loop Associating EGR1 and PDGFA Promotes Proliferation and Self-renewal in Glioblastoma Stem Cells

Abstract

Glioblastomas are the most common primary brain tumors, highly vascularized, infiltrating, and resistant to current therapies. This cancer leads to a fatal outcome in less than 18 months. The aggressive behavior of glioblastomas, including resistance to current treatments and tumor recurrence, has been attributed to glioma stemlike/progenitor cells. The transcription factor EGR1 (early growth response 1), a member of a zinc finger transcription factor family, has been described as tumor suppressor in gliomas when ectopically overexpressed. Although EGR1 expression in human glioblastomas has been associated with patient survival, its precise location in tumor territories as well as its contribution to glioblastoma progression remain elusive. In the present study, we show that EGR1-expressing cells are more frequent in high grade gliomas where the nuclear expression of EGR1 is restricted to proliferating/progenitor cells. We show in primary cultures of glioma stemlike cells that EGR1 contributes to stemness marker expression and proliferation by orchestrating a PDGFA-dependent growth-stimulatory loop. In addition, we demonstrate that EGR1 acts as a positive regulator of several important genes, including SHH, GLI1, GLI2, and PDGFA, previously linked to the maintenance and proliferation of glioma stemlike cells.

MEIS homeodomain proteins facilitate PARP1/ARTD1-mediated eviction of histone H1

“…Interestingly, several of these genes were already linked to GBM. Example genes include heme oxygenase 1 ( Hmox1 ) and platelet-derived growth factor α ( Pdgfα ), which are associated with disease progression or known to promote proliferation of GBM tumor-initiating cells, respectively ( Ghosh et al, 2016 ; Sakakini et al, 2016 ). Most of the significantly down-regulated genes, in contrast, were related to GO terms consistent with neurogenesis, including “nervous system development” or “regulation of cell differentiation” and were significantly correlated with the UniGene Expression term “brain” (P = 1.703e -08 , Fisher’s exact test; Fig.…”

Targeting neuronal activity-regulated neuroligin-3 dependency in high-grade glioma

“…Genes involved in cell proliferation were upregulated, as were numerous genes known to promote malignancy in glioma, including PDGFA 8–10 , TTYH1 11 and several potassium channel genes 12 (Extended Data Fig. 3).…”

Targeting neuronal activity-regulated neuroligin-3 dependency for high-grade glioma therapy

“…5). We also found significant upregulation of genes known to promote malignancy in glioma, including increased expression of platelet-derived growth factor alpha (PDGFA), a growth factor strongly implicated in glioma growth and progression 13–15 , and several potassium channel genes, recently shown to play a role in DIPG cell viability 16 . In addition to the expected upregulation of NLGN3 expression itself 1 , a number of genes involved in synapse function were also upregulated following NLGN3 exposure (Extended Data Fig.…”