Transcription factors FOXG1 and Groucho/TLE promote glioblastoma growth

Abstract

Glioblastoma (GBM) is the most common and deadly malignant brain cancer, with a median survival of less than two years. GBM displays a cellular complexity that includes brain tumour-initiating cells (BTICs), which are considered as potential key targets for GBM therapies. Here we show that the transcription factors FOXG1 and Groucho/TLE are expressed in poorly differentiated astroglial cells in human GBM specimens and in primary cultures of GBM-derived BTICs, where they form a complex. FOXG1 knockdown in BTICs causes downregulation of neural stem/progenitor and proliferation markers, increased replicative senescence, upregulation of astroglial differentiation genes, and decreased BTIC-initiated tumour growth upon intracranial transplantation into host mice. These effects are phenocopied by Groucho/TLE knockdown or dominant-inhibition of the FOXG1:Groucho/TLE complex. These results provide evidence that transcriptional programs regulated by FOXG1 and Groucho/TLE are important for BTIC-initiated brain tumour growth, implicating FOXG1 and Groucho/TLE in GBM tumorigenesis.

Elevated FOXG1 and SOX2 in glioblastoma enforces neural stem cell identity through transcriptional control of cell cycle and epigenetic regulators

“…A GFP reporter construct was inserted at the safe harbor AAVS1 locus in both parental control cells and the FOXG1 −/− clone to enable monitoring of cells following xenotransplantation. Consistent with the previously reported shRNA knockdown results (Verginelli et al 2013), we saw a failure of the FOXG1 −/− G7-A cells to form tumors on transplantation into immunocompromised mice (n = 4) (Fig. 7C).…”

“…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.…”

“…Previous studies using shRNA knockdown of FOXG1 have suggested an important role in promoting tumor growth (Verginelli et al 2013). CRISPR/Cas9 provides new opportunities for decisive functional genetic studies in primary human GBM stem cells.…”

“…Although FOXG1 is not genetically amplified in glioma, FOXG1 mRNA levels in primary tumors are inversely correlated with patient survival (Verginelli et al 2013). Recently, Liu et al (2015) demonstrated that the oncogenic EGFR truncation (EGFRvIII)-found in a significant proportion of "classical" subtype GBMs-operates in part by triggering expression of FOXG1.…”

Cancer stem cells in glioblastoma

“…CSC regulation converges on MYC, which occurs in the presence of MYC-mediated cancer cell survival and proliferation programs Zheng et al 2008;Wurdak et al 2010;Chan et al 2012;Fang et al 2014). Additional transcription factors have been identified as important for CSC identity, including STAT3 (Sherry et al 2009), SOX2 (Gangemi et al 2009), FOXM1 (Joshi et al 2013), FOXG1 (Verginelli et al 2013), GLI1 (Clement et al 2007), ASCL1 (Rheinbay et al 2013), ZFX , NANOG (Zbinden et al 2010), and ZFHX4 (Chudnovsky et al 2014), which recruit necessary chromatin remodeling factors to promote maintenance of the glioma CSC state. By using epigenome-wide mapping of cellular chromatin state, Suva et al (2014) identified a core set of four transcription factors in proneural GBM able to reprogram differentiated tumor cells into glioma CSCs.…”