HIF-2α Promotes Hypoxic Cell Proliferation by Enhancing c-Myc Transcriptional Activity

Gordan, John D.; Bertout, Jessica A.; Hu, Cheng-Jun; Diehl, J. Alan; Simon, M. Celeste

doi:10.1016/j.ccr.2007.02.006

Cited by 678 publications

(640 citation statements)

References 48 publications

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“…HIF-2a has been discussed as a critical mediator of renal tumorigenesis by enhancing c-Myc activity in vivo, particularly in renal cell carcinoma exclusively expressing this isoform, and overexpression of HIF-2a increased xenografted tumor growth (Raval et al, 2005;Gordan et al, 2007Gordan et al, , 2008. However, we did not observe any changes in c-Myc-dependent transcription in MCF-7 cells preferentially expressing HIF-2a (Supplementary Figure S5), implying that the HIF-2a/c-Myc interplay probably is tissue-specific.…”

Section: Discussionmentioning

confidence: 99%

Non-canonical HIF-2α function drives autonomous breast cancer cell growth via an AREG–EGFR/ErbB4 autocrine loop

et al. 2011

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Tumor progression is intrinsically tied to the clonal selection of tumor cells with acquired phenotypes allowing to cope with a hostile microenvironment. Hypoxiainducible factors (HIFs) master the transcriptional response to local tissue hypoxia, a hallmark of solid tumors. Here, we report significantly longer patient survival in breast cancer with high levels of HIF-2a. Amphiregulin (AREG) and WNT1-inducible signaling pathway protein-2 (WISP2) expression was strongly HIF2a-dependent and their promoters were particularly responsive to HIF-2a. The endogenous AREG promoter recruited HIF-2a in the absence of a classical HIF-DNA interaction motif, revealing a novel mechanism of gene regulation. Loss of AREG expression in HIF-2a-depleted cells was accompanied by reduced activation of epidermal growth factor (EGF) receptor family members. Apparently opposing results from patient and in vitro data point to an HIF-2a-dependent auto-stimulatory tumor phenotype that, while promoting EGF signaling in cellular models, increased the survival of diagnosed and treated human patients. Our findings suggest a model where HIF2a-mediated autocrine growth signaling in breast cancer sustains a state of cellular self-sufficiency, thereby masking unfavorable microenvironmental growth conditions, limiting adverse selection and improving therapy efficacy. Importantly, HIF-2a/AREG/WISP2-expressing tumors were associated with luminal tumor differentiation, indicative of a better response to classical treatments. Shifting the HIF-1/2a balance toward an HIF-2-dominated phenotype could thus offer a novel approach in breast cancer therapy.

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Section: Discussionmentioning

confidence: 99%

Non-canonical HIF-2α function drives autonomous breast cancer cell growth via an AREG–EGFR/ErbB4 autocrine loop

et al. 2011

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“…While structurally and functionally similar, HIF-1α and HIF-2α appear to exert different biological functions, as demonstrated in studies using knockout mice (Hu et al, 2003). For example, while HIF-1α antagonizes c-Myc function, inhibiting renal cell carcinoma (RCC) growth, HIF-2α promotes cell cycle progression in hypoxic RCC and many other cell lines (Gordan et al, 2007). Interestingly, the most distantly related isoform, HIF-3α, appears to antagonize HRE-dependent gene expression, suggesting a possible negative influence on hypoxiainduced gene expression.…”

Section: Regulation Of Vegf Expressionmentioning

confidence: 99%

Vascular endothelial growth factor in eye disease

Penn

Madan

Caldwell

et al. 2008

Progress in Retinal and Eye Research

595

503

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Collectively, angiogenic ocular conditions represent the leading cause of irreversible vision loss in developed countries. In the U.S., for example, retinopathy of prematurity, diabetic retinopathy and age-related macular degeneration are the principal causes of blindness in the infant, working age and elderly populations, respectively. Evidence suggests that vascular endothelial growth factor (VEGF), a 40 kDa dimeric glycoprotein, promotes angiogenesis in each of these conditions, making it a highly significant therapeutic target. However, VEGF is pleiotropic, affecting a broad spectrum of endothelial, neuronal and glial behaviors, and confounding the validity of anti-VEGF strategies, particularly under chronic disease conditions. In fact, among other functions VEGF can influence cell proliferation, cell migration, proteolysis, cell survival and vessel permeability in a wide variety of biological contexts. This article will describe the roles played by VEGF in the pathogenesis of retinopathy of prematurity, diabetic retinopathy and age-related macular degeneration. The potential disadvantages of inhibiting VEGF will be discussed, as will the rationales for targeting other VEGF-related modulators of angiogenesis.

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“…Likewise, another cyclin-dependent kinase inhibitor gene CDKN1B (encoding p27 kip1 ), also suppressed by c-Myc, can be upregulated by hypoxia by a similar mechanism. 28,37 Thus, HIF-1a antagonizes repressive c-Myc activity for gene activation. It should be noted that unlike c-Myc displacement from the MSH2 promoter (see below), the biochemistry of c-Myc displacement by HIF-1a in the CDKN1A and CDKN1B gene promoters has not been well characterized.…”

Section: Hif-1a Regulates Cell Cycle and Dna Repair Genes By Counteramentioning

confidence: 99%

“…Furthermore, it stands to reason that HIF-1a might displace c-Myc from Sp1 more readily than from an E-box element, assuming a stronger binding affinity to the DNA sequence. However, more quantitative analyses of c-Myc binding to the E-box element in c-Myc-activated genes such as ODC, CCND2, and E2F1 (encoding ornithine decarboxylase 1, cyclin D2, and E2F transcription factor 1, respectively) have shown decreased c-Myc promoter occupancy under hypoxia, 28 suggesting the occurrence of c-Myc displacement from the E-box element, albeit to a lesser extent. Furthermore, HIF-1a also induces a shift in the heterocomplex formation from activating c-Myc-Max to repressive Mad1-Max or Mxi1-Max, thereby further contributing to the inactivation of c-Myc target genes.…”

Section: Hif-1a Regulates Cell Cycle and Dna Repair Genes By Counteramentioning

confidence: 99%

“…Recent studies, however, have begun to shed new light on these questions by unraveling the intricate role of the protooncoprotein c-Myc in relation to HIF-a in adaptation to the tumor microenvironment. [26][27][28][29] c-Myc plays a central role in a transcription factor network that regulates cellular growth, differentiation, apoptosis, and metabolism. 30,31 It is frequently overexpressed in human cancers because of genetic rearrangements such as gene amplifications and chromosomal translocation.…”

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confidence: 99%

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Carrot and stick: HIF-α engages c-Myc in hypoxic adaptation

Huang

2008

Cell Death Differ

123

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The past decade of research on hypoxic responses has provided a considerable understanding of how cells respond to hypoxic stress at the molecular level, thanks to the identification and molecular cloning of the hypoxia-inducible transcription factor, HIF-1a. Numerous target genes have since been identified to account for various aspects of the hypoxic response, including angiogenesis and glycolysis. Yet, fundamental questions remain regarding the mechanisms by which hypoxia controls cell proliferation, genetic instability, mitochondrial biogenesis, and oxidative respiration in cancer cells. Although the protooncoprotein c-Myc appears to be the diametrical opposite of HIF-1a in most of these processes, recent studies indicate that c-Myc is an integral part of the HIF-a-c-Myc molecular pathway in the hypoxic response. It has been shown that HIF-a engages with Myc by various mechanisms to achieve oxygen homeostasis for cell survival. This article focuses on the intricate roles of cMyc in the hypoxic response, discusses various mechanisms controlling c-Myc activity by HIF-a for the regulation of hypoxiaresponsive genes, and emphasizing the outcome of gene expression apparently dependent upon hypoxic conditions, cellular context, and gene promoter. Solid tumors tend to develop hypoxia (oxygen deprivation), which arises out of the rapid cell proliferation that outstrips the supply of oxygen from the blood vessels. Consequently, tumor hypoxia activates hypoxia-inducible factor (HIF)-1a and HIF-2a, 1,2 two of the well-characterized hypoxia-inducible transcription factors critical for tumor angiogenesis, glycolysis, and metastasis. [3][4][5] Under physiological conditions, hypoxia activates the ubiquitous HIF-1a, whereas HIF-2a expression is more tissue specific. Yet in human cancers of diverse origins, both HIF-1a and HIF-2a, referred to collectively hereinafter as HIF-a, are frequently overexpressed and activated.Hypoxia-inducible factor-a is the regulatory subunit of the HIF heterodimeric complex paired with the aryl hydrocarbon receptor nuclear translocator (ARNT, also known as HIF-1b). 6 They belong to the Per-ARNT-Sim (PAS) superfamily 7 of transcription factors containing basic helix-loop-helix domains (Figure 1a). Whereas PAS domains confer target gene specificity through protein-protein interactions, 8 the oxygendependent degradation domain, unique to HIF-a, mediates oxygen-dependent proteolysis. 9 As such, despite constitutive transcription and translation of the HIF1A and EPAS1 genes (encoding HIF-1a and HIF-2a, respectively), HIF-a protein levels remain low in oxygenated conditions because of proteolysis via the ubiquitin-proteasome pathway. 9-12 HIF-a degradation requires the pVHL-containing E3 ubiquitin ligase, 13-15 which recognizes two hydroxylated proline residues of HIF-a (P402 and P564 in HIF-1a; Figure 1a). [16][17][18] HIFa is hydroxylated by three prolyl hydroxylases, EglN1, EglN2, and EglN3 (better known as PHD2, PHD1, and PHD3, respectively), which sense oxygen tension and transduce oxygen signal...

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HIF-2α Promotes Hypoxic Cell Proliferation by Enhancing c-Myc Transcriptional Activity

Cited by 678 publications

References 48 publications

Non-canonical HIF-2α function drives autonomous breast cancer cell growth via an AREG–EGFR/ErbB4 autocrine loop

Non-canonical HIF-2α function drives autonomous breast cancer cell growth via an AREG–EGFR/ErbB4 autocrine loop

Vascular endothelial growth factor in eye disease

Carrot and stick: HIF-α engages c-Myc in hypoxic adaptation

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