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The role of factor inhibiting HIF (FIH-1) in inhibiting HIF-1 transcriptional activity in glioblastoma multiforme.
- Source :
-
PloS one [PLoS One] 2014 Jan 23; Vol. 9 (1), pp. e86102. Date of Electronic Publication: 2014 Jan 23 (Print Publication: 2014). - Publication Year :
- 2014
-
Abstract
- Glioblastoma multiforme (GBM) accounts for about 38% of primary brain tumors in the United States. GBM is characterized by extensive angiogenesis induced by vascular growth factors and cytokines. The transcription of these growth factors and cytokines is regulated by the Hypoxia-Inducible-Factor-1(HIF-1), which is a key regulator mediating the cellular response to hypoxia. It is known that Factor Inhibiting HIF-1, or FIH-1, is also involved in the cellular response to hypoxia and has the capability to physically interact with HIF-1 and block its transcriptional activity under normoxic conditions. Delineation of the regulatory role of FIH-1 will help us to better understand the molecular mechanism responsible for tumor growth and progression and may lead to the design of new therapies targeting cellular pathways in response to hypoxia. Previous studies have shown that the chromosomal region of 10q24 containing the FIH-1 gene is often deleted in GBM, suggesting a role for the FIH-1 in GBM tumorigenesis and progression. In the current study, we found that FIH-1 is able to inhibit HIF-mediated transcription of GLUT1 and VEGF-A, even under hypoxic conditions in human glioblastoma cells. FIH-1 has been found to be more potent in inhibiting HIF function than PTEN. This observation points to the possibility that deletion of 10q23-24 and loss or decreased expression of FIH-1 gene may lead to a constitutive activation of HIF-1 activity, an alteration of HIF-1 targets such as GLUT-1 and VEGF-A, and may contribute to the survival of cancer cells in hypoxia and the development of hypervascularization observed in GBM. Therefore FIH-1 can be potential therapeutic target for the treatment of GBM patients with poor prognosis.
- Subjects :
- Animals
Brain Neoplasms genetics
Cell Hypoxia
Cell Line, Tumor
E1A-Associated p300 Protein metabolism
Glioblastoma genetics
Glucose Transporter Type 1 genetics
Glucose Transporter Type 1 metabolism
Humans
Mice
Mice, Nude
Neoplasm Transplantation
Vascular Endothelial Growth Factor A genetics
Vascular Endothelial Growth Factor A metabolism
Brain Neoplasms metabolism
Gene Expression Regulation, Neoplastic
Glioblastoma metabolism
Hypoxia-Inducible Factor 1, alpha Subunit physiology
Mixed Function Oxygenases physiology
Repressor Proteins physiology
Transcription, Genetic
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 9
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 24465898
- Full Text :
- https://doi.org/10.1371/journal.pone.0086102