Abstract
Grade IV astrocytoma or glioblastoma has a poor clinical outcome that can be linked to hypoxia, invasiveness and active vascular remodeling. It has recently been suggested that hypoxia-inducible factors, Hifs, increase glioma growth and aggressiveness [1], [2], [3]. Here, we tested the hypothesis that Egl 9 homolog 3 (Egln3), a prolyl-hydroxylase that promotes Hif degradation, suppresses tumor progression of human and rodent glioma models. Through intracranial tumorigenesis and in vitro assays, we demonstrate for the first time that Egln3 was sufficient to decrease the kinetics of tumor progression and increase survival. We also find that Klf5, a transcription factor important to vascular remodeling, was regulated by hypoxia in glioma. An analysis of the tumor vasculature revealed that elevated Egln3 normalized glioma capillary architecture, consistent with a role for Egln3 in eliciting decreases in the production of Hif-regulated, angiogenic factors. We also find that the hydroxylase-deficient mutant, Egln3H196A partially maintained tumor suppressive activity. These results highlight a bifurcation of Egln3 signaling and suggest that Egln3 has a non-hydroxylase-dependent function in glioma. We conclude that Egln3 is a critical determinant of glioma formation and tumor vascular functionality.
Highlights
Glioblastoma is a highly invasive, fast-growing cancer, classified by hypoxia, necrosis and the active formation of intra-tumor blood vessels [4]
hypoxia-inducible factors (Hifs) participate in maintaining the transcription of Oct4, a gene widely expressed within glioma cells, and are causal to aggressive glioma growth and progression [1,2,3,18,19,20,21,22]
We evaluated whether the expression of any member of the Egln prolyl-hydroxylase family correlated with the Hif-expression pattern during the hypoxic response of glioma cells
Summary
Glioblastoma is a highly invasive, fast-growing cancer, classified by hypoxia, necrosis and the active formation of intra-tumor blood vessels [4]. For a variety of tumor types, high levels of Hif-1a and Hif-2a are tightly correlated with malignancy, invasiveness, metastasis and vascular density [10,11,12,13,14,15,16]. Hif-2a promotes tumor-initiation, the up-regulation of pro-angiogenic factors such as Vegf and expression of the embryonic stem cell gene, Oct4 [2,18,19,20,21,22]. These data highlight Hifs as potential targets for dismantling the initiation and vascularization potential of glioma and raises the possibility that endogenously occurring Hif inhibitors could be employed to antagonize tumor progression
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