Gordan JD, Simon MC.. Hypoxia-inducible factors: central regulators of the tumor phenotype. Curr Opin Genet Dev 17: 71-77

Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, PA, USA.
Current Opinion in Genetics & Development (Impact Factor: 7.57). 03/2007; 17(1):71-7. DOI: 10.1016/j.gde.2006.12.006
Source: PubMed


Low oxygen levels are a defining characteristic of solid tumors, and responses to hypoxia contribute substantially to the malignant phenotype. Hypoxia-induced gene transcription promotes characteristic tumor behaviors, including angiogenesis, invasion, metastasis, de-differentiation and enhanced glycolytic metabolism. These effects are mediated, at least in part, by targets of the hypoxia-inducible factors (HIFs). The HIFs function as heterodimers comprising an oxygen-labile alpha-subunit and a stable beta-subunit also referred to as ARNT. HIF-1alpha and HIF-2alpha stimulate the expression of overlapping as well as unique transcriptional targets, and their induction can have distinct biological effects. New targets and novel mechanisms of dysregulation place the HIFs in an ever more central role in tumor biology and have led to development of pharmacological inhibitors of their activity.

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    • "There they can act as functional transcription factors after heterodimerization with constitutively expressed HIF-b subunits [10]. The functional HIF heterodimer binds to the hypoxia responsive elements (HREs) present in gene promoters, thereby regulating downstream target genes [11]. Three HIF isoforms have been described (HIF-1, -2 and -3). "
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    ABSTRACT: The α1,2-fucosyltransferase activity in pancreatic tumors is much lower compared to normal pancreatic tissue. Here we here show that hypoxia inducible factor (HIF) 1α is constitutively expressed in the pancreatic cancer cell lines Pa-Tu-8988S and Pa-Tu-8988T and suppresses the expression of the α1,2-fucosyltransferase genes FUT1 and FUT2. Down regulation of HIF-1α expression resulted in elevated FUT1 and FUT2 transcript levels and an increased expression of α1,2-fucosylated glycan structures on the surface of these cells. In conclusion, our data are the first to identify HIF-1α as a suppressor of FUT1/2 expression, thereby regulating α1,2-fucosylation of cell-surface glycans. Copyright © 2015. Published by Elsevier B.V.
    FEBS letters 07/2015; 589(18). DOI:10.1016/j.febslet.2015.07.035 · 3.17 Impact Factor
    • "In hypoxia, prolyl hydroxylation is inhibited, resulting in HIF-a stabilization and dimerization with aryl hydrocarbon receptor nuclear transactivator (ARNT) (Wang et al., 1995). Consequently, VHL loss of function results in constitutive activation of HIF-a, which promotes tumorigenesis through transcriptional activation of genes involved in angiogenesis, invasion, metastasis, and metabolism (Gordan and Simon, 2007). Constitutive activation of HIF transcription factors is thought to be a primary driving force of metabolic reprogramming in ccRCC. "
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    ABSTRACT: Long believed to be a byproduct of malignant transformation, reprogramming of cellular metabolism is now recognized as a driving force in tumorigenesis. In clear cell renal cell carcinoma (ccRCC), frequent activation of HIF signaling induces a metabolic switch that promotes tumorigenesis. Here, we demonstrate that PGC-1α, a central regulator of energy metabolism, is suppressed in VHL-deficient ccRCC by a HIF/Dec1-dependent mechanism. In VHL wild-type cells, PGC-1α suppression leads to decreased expression of the mitochondrial transcription factor Tfam and impaired mitochondrial respiration. Conversely, PGC-1α expression in VHL-deficient cells restores mitochondrial function and induces oxidative stress. ccRCC cells expressing PGC-1α exhibit impaired tumor growth and enhanced sensitivity to cytotoxic therapies. In patients, low levels of PGC-1α expression are associated with poor outcome. These studies demonstrate that suppression of PGC-1α recapitulates key metabolic phenotypes of ccRCC and highlight the potential of targeting PGC-1α expression as a therapeutic modality for the treatment of ccRCC. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 06/2015; 12(1). DOI:10.1016/j.celrep.2015.06.006 · 8.36 Impact Factor
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    • "Under normoxia, HIF1α is constitutively synthesized and hydroxylated by prolyl hydroxylases (PHDs). Hydroxylated HIF1α is recognized by the von Hippel-Lindau protein and its associated ubiquitinase, resulting in proteolytic degradation in proteasomes [61] [62]. Under hypoxia, reduced oxygen supply diminishes the activity of PHDs, which are further inhibited by ROS released from stressed mitochondria that operate under reduced OXPHOS. "
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    ABSTRACT: Metabolic reprogramming and altered bioenergetics have become emerged as a hallmark of cancer and an area of active basic and translational cancer research. Drastically upregulated glucose transport and metabolism in most cancers regardless the oxygen supply, a phenomenon called the Warburg effect, is one of major focuses of the research. Warburg speculated that cancer cells, due to defective mitochondrial oxidative phosphorylation (OXPHOS), switch to glycolysis for ATP synthesis, even in the presence of oxygen. Studies in the recent decade indicated that while glycolysis is indeed drastically upregulated in almost all cancer cells, mitochondrial respiration continues to operate normally at rates proportional to oxygen supply. There is no OXPHOS-to-glycolysis switch but rather upregulation of glycolysis. Furthermore, upregulated glycolysis appears to be for synthesis of biomass and reducing equivalents in addition to ATP production. The new finding that a significant amount of glycolytic intermediates are diverted to the pentose phosphate pathway (PPP) for production of NADPH has profound implications in how cancer cells use the Warburg effect to cope with reactive oxygen species (ROS) generation and oxidative stress, opening the door for anti-cancer interventions taking advantage of this. Recent findings in the Warburg effect and its relationship with ROS and oxidative stress controls will be reviewed. Cancer treatment strategies based on these new findings will be presented and discussed.
    Free Radical Biology and Medicine 09/2014; 79. DOI:10.1016/j.freeradbiomed.2014.08.027 · 5.74 Impact Factor
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