Truncated Glioma-Associated Oncogene Homolog 1 (tGLI1) Mediates Mesenchymal Glioblastoma via Transcriptional Activation of CD44

Abstract

The molecular pathways driving mesenchymal glioblastoma (GBM) are still not well understood. We report here that truncated glioma-associated oncogene homolog 1 (tGLI1) is a tumor-specific transcription factor that facilitates GBM growth, is enriched in the mesenchymal subtype of GBM and glioma stem cells (GSC), and promotes mesenchymal GSC by upregulating transcription of CD44. In an orthotopic GBM xenograft mouse model, tGLI1-overexpressing tumors grew more aggressively with increased proliferation and angiogenesis compared with control and GLI1-overexpressing xenografts. tGLI1 was highly expressed in GBM clinical specimens but undetectable in normal brains, whereas GLI1 was expressed in both tissues. A tLI1 activation signature (tGAS) correlated with glioma grade, tumor angiogenesis, and poor overall survival, and GBMs with high tGAS were enriched with mesenchymal GBM/GSC gene signatures. Neurospheres contained increased levels of tGLI1, but not GLI1, compared with the monolayer culture; mesenchymal GSC expressed more tGLI1 than proneural GSC. Ectopic tGLI1 expression enhanced the ability of mesenchymal GSC to yield neurospheres and to form tumors in mouse brains. Selective tGLI1 knockdown reduced neurosphere formation of GBM cells. tGLI1 bound to and transactivated the promoter of the CD44 gene, a marker and mediator for mesenchymal GSC, leading to its expression. Collectively, these findings advance our understanding of GBM biology by establishing tGLI1 as a novel transcriptional activator of CD44 and a novel mediator of mesenchymal GBM and GSC. These findings highlight the role of a tumor-specific gain-of-function transcription factor tGLI1 in mesenchymal glioma stem cell maintenance and mesenchymal GBM growth. .

NEAT1 is Required for the Expression of the Liver Cancer Stem Cell Marker CD44

“…In HuH7 and mNeat1v1-overexpressing HepG2 cells, the expression of CD44s was observed, while other splicing variants were not detected. It has been reported that CD44 expression in tumor cells is regulated by transcription factors and miRNAs [33][34][35][36][37]. A lncRNA, gastric adenocarcinoma predictive long intergenic noncoding RNA (GAPLINC), also induces CD44 expression by suppressing miR-221, a CD44-targeting miRNA [33].…”

Hedgehog Signaling and Truncated GLI1 in Cancer

“…GLI1 proteins regulate the expression of the pluripotency factors Nanog, octamer binding transcription factor 4 (OCT4), SOX2, WNT-2, CD44, and Kruppel-like factor 4 (KLF4) [148,165,167,168]. Recently, we have shown the novel tGLI1 isoform to promote the glioma stem cell population via upregulation of CD44 and the breast cancer stem cell population through upregulation of CD44, Nanog, OCT4, and Sox2 (Section 6) [31,33]. These data demonstrate that amplified SHH signaling is important for the self-renewal and maintenance of CSCs.…”

Splicing Dysregulation as Oncogenic Driver and Passenger Factor in Brain Tumors

“…Indeed, tGLI1 sustains GBM angiogenesis and growth by promoting the expression of VEGFA and VEGF receptor 2 (VEGFR2) in both GBM and MB [79] (Table 2). Furthermore, tGLI1 is predominantly activated in the highly aggressive mesenchymal subtype of GBM and in GSCs, suggesting its contribution to the acquisition of a more malignant GBM phenotype [83].…”