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Fibroblast growth factor-23 (FGF23) is a circulating hormone that acts to correct hyperphosphatemic states by inhibiting renal phosphate reabsorption and to prevent hypervitaminosis D by feedback repressing 1, 25-dihydroxyvitamin D3 (1,25(OH)2D3) biosynthesis. FGF23 gene expression in the osteoblast/osteocyte is induced by the nuclear vitamin D receptor (VDR) bound to 1,25(OH)2D3, but cycloheximide sensitivity of this induction suggests that it may occur largely via secondary mechanisms requiring cooperating transcription factors. We therefore sought to identify 1,25(OH)2D3-regulated transcription factors that might impact FGF23 expression. Although neither leptin nor interleukin-6 (IL-6) alone affects FGF23 expression, leptin treatment was found to potentiate 1,25(OH)2D3 upregulation of FGF23 in UMR-106 cells, whereas IL-6 treatment blunted this upregulation. Genomic analyses revealed conserved binding sites for STATs (signal transduction mediators of leptin and IL-6 action) along with transcription factor ETS1 in human and other mammalian FGF23 genes. Further, STAT3, STAT1, ETS1, and VDR mRNAs were induced in a dose-dependent manner by 1,25(OH)2D3 in UMR-106 cells. Bioinformatic analysis identified nine potential VDREs in a genomic interval containing human FGF23. Six of the putative VDREs were capable of mediating direct transcriptional activation of a heterologous reporter gene when bound by a 1,25(OH)2D3-liganded VDR complex. A model is proposed wherein 1,25(OH)2D3 upregulates FGF23 production directly via multiple VDREs and indirectly via induction of STAT3, ETS1, and VDR transcription factors that are then activated via cell surface and intracellular signaling to cooperate in the induction of FGF23 through DNA looping and generation of euchromatin architecture.

A population of tumorigenic, chemoresistant, and radioresistant cancer stem cells is postulated to contribute to the aggressive and fatal clinical course of glioblastomas. Activation of the Hedgehog (HH) pathway and increased expression of its downstream effector GLI1 are driving factors of glioma tumorigenicity and glioma stem cell (GSC) biology. In this study, we describe a dependence of insulin-like growth factor (IGF) signaling on active HH/GLI1 in GSCs. Insulin receptor substrate 1 (IRS1) was identified as a target of the GLI1 transcription factor and inhibition of GLI1 was sufficient to obstruct IRS1 protein expression and IGF-I induced mitogen-activated protein kinase (MAPK) activation. Suppression of GLI1 activity decreased the responsiveness of GSCs to IGF-I stimulation and constrained IGF-I dependent GSC proliferation, clonogenicity, invasion, and angiogenesis. In addition, blockade of the HH/GLI1 and IGF pathways countered the intrinsic and acquired resistance of GSCs to temozolomide. These results provide further insight into the oncogenic mechanisms of the HH pathway in glioblastoma and demonstrate a cooperative signaling axis between the HH/GLI1 and IGF pathways to propagate malignant GSC phenotypes.

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