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

Nathalie Sakakini,Laurent Turchi,Aurélie Bergon,Hélène Holota,Samah Rekima,Fabrice Lopez,Philipe Paquis,Fabien Almairac,Denys Fontaine,Nathalie Baeza-Kallee,Ellen Van Obberghen-Schilling,Marie-Pierre Junier,Hervé Chneiweiss,Dominique Figarella-Branger,Fanny Burel-Vandenbos,Jean Imbert,Thierry Virolle

doi:10.1074/jbc.m116.720698

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.

Highlights

Glioblastomas (GBM)4 are the most common form of primary brain tumors afflicting adult patients of all ages [1]
Nuclear Expression of EGR1 Is Frequent in GBM and Restricted to Proliferating/Progenitor Cells—To assess whether EGR1 might be associated with features of infiltration and malignancy of glial tumors, we sought to compare its expression between pilocytic astrocytomas (PA), a non-infiltrating slow growing tumor considered benign, and GBM, aggressive tumors, always infiltrating and fast growing
Due to its ability to regulate a large panel of genes, EGR1 is a transcription factor capable of controlling a variety of important cellular events, such as cell growth or apoptosis [8]

Summary

Introduction

Glioblastomas (GBM) are the most common form of primary brain tumors afflicting adult patients of all ages [1]. We have previously demonstrated a positive regulatory feed-forward control between ERK and NOTCH pathways, which relies on miR-18a*-mediated repression of delta-like 3 protein expression, a ligand inhibitor of NOTCH [5]. In this mechanism, activated NOTCH1 is required for sustained ERK activation, which is necessary to turn on the SHH (sonic hedgehog)-GLI-NANOG signaling network, essential for the maintenance of GSC proliferation [5,6,7]. We report here that EGR1-positive cells are frequent in glioblastomas In these tumors, nuclear localization of EGR1 is restricted to proliferating cells and strongly associated with OLIG2ϩ stemlike or progenitor cells. We show in addition its contribution for the direct regulation of a panel of genes, such as SHH, GLI1, GLI2, and PDGFA, previously associated with stemness and cell proliferation

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Conclusion