Suppression of glioma progression by Egln3.
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, Egln3(H196A) 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.
Department of Molecular and Cell Biology, Division of Cell and Developmental Biology, University of California, Berkeley, California, United States of America.
Vicki A
VA
Sciorra
Michael A
MA
Sanchez
Akemi
A
Kunibe
Andrew E
AE
Wurmser
D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D004268:DNA-Binding Proteins / Q000378:metabolism; D049308:Dioxygenases / Q000378:metabolism / Q000502:physiology*; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis / Q000378:metabolism; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D017874:Immediate-Early Proteins / Q000378:metabolism; D007700:Kinetics; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D051379:Mice; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D050814:Octamer Transcription Factor-3 / Q000378:metabolism; D051381:Rats; D016896:Treatment Outcome
D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017874:Immediate-Early Proteins; C492214:KLF5 protein, human; D051741:Kruppel-Like Transcription Factors; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; D049308:Dioxygenases; C488894:EGLN3 protein, human; C087100:Egln3 protein, rat; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases