A Novel Splice Variant of GLI1 That Promotes Glioblastoma Cell Migration and Invasion

The family of GLI zinc finger transcription factors regulates the expression of genes involved in many important cellular processes, notably embryonal development and cellular differentiation. The glioma-associated oncogene homologue 1 (GLI1) isoform, in particular, has attracted much attention because of its frequent activation in many human cancers and its interactions with other signaling pathways, such as those mediated by K-RAS, transforming growth factor-beta, epidermal growth factor receptor, and protein kinase A. Here, we report the identification of a novel truncated GLI1 splice variant, tGLI1, with an in-frame deletion of 123 bases (41 codons) spanning the entire exon 3 and part of exon 4 of the GLI1 gene. Expression of tGLI1 is undetectable in normal cells but is high in glioblastoma multiforme (GBM) and other cancer cells. Although tGLI1 undergoes nuclear translocalization and transactivates GLI1-binding sites similar to GLI1, unlike GLI1, it is associated with increased motility and invasiveness of GBM cells. Using microarray analysis, we showed > 100 genes to be differentially expressed in tGLI1-expressing compared with GLI1-expressing GBM cells, although both cell types expressed equal levels of known GLI1-regulated genes, such as PTCH1. We further showed one of the tGLI1 up-regulated genes, CD24, an invasion-associated gene, to be required for the migratory and invasive phenotype of GBM cells. These data provide conclusive evidence for a novel gain-of-function GLI1 splice variant that promotes migration and invasiveness of GBM cells and open up a new research paradigm on the role of the GLI1 pathway in malignancy. [Cancer Res 2009; 69(17):6790-8]