Target gene selectivity of hypoxia-inducible factor-α in renal cancer cells is conveyed by post-DNA-binding mechanisms

Lau, KW; Tian, Ym-M.; Raval, R.R.; Ratcliffe, Peter J.; Pugh, Christopher W.

doi:10.1038/sj.bjc.6603675

Cited by 93 publications

(109 citation statements)

References 35 publications

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“…HIF-2a is associated with luminal breast cancer DP Stiehl et al target genes Lau et al, 2007), further supported by the fact that the DNA-binding basic helixloop-helix as well as the Per-ARNT-Sim domains are 487% conserved between both transcription factors. We constructed HIF-1a/HIF-2a hybrid expression plasmids (designated H1a/H2a and H2a/H1a, respectively) with interchanged basic helix-loop-helix and Per-ARNT-Sim portions as schematically depicted in Figure 5d.…”

Section: Immunohistochemical Analyses Of Ca9 and Glut1mentioning

confidence: 94%

“…However, expression analyses in a renal clear cell carcinoma-derived cell line deficient for HIF-1a revealed preserved hypoxic induction of many known HIF target genes, indicating that effectively both HIF-a isoforms contribute to hypoxia-induced transcription (Hu et al, 2003). Domain-swapping experiments between HIF-1a and HIF-2a provided experimental evidence for the interchangeability of the DNA-binding regions of either isoform and attributed gene selectivity to the N-terminal transactivation domains of HIF-a Lau et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

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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: Immunohistochemical Analyses Of Ca9 and Glut1mentioning

confidence: 94%

Section: Introductionmentioning

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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“…By swapping protein domains between HIF1α and HIF2α, several groups demonstrated that this transcriptional specificity resided in the N-terminal activation domain (N-TAO), suggesting that differential interactions with transcriptional co-factors likely determine differential gene activation 29,30 . Recently, multiple groups have used chromatin immunoprecipitation coupled to tiled microarrays (ChiP-chip) to assess HIFα binding across the genome 31-35 .…”

Section: Direct Regulation Of Gene Expression By Hif1α and Hif2αmentioning

confidence: 99%

HIF1α and HIF2α: sibling rivalry in hypoxic tumour growth and progression

Keith¹,

Johnson²,

Simon³

2011

Nat Rev Cancer

1,508

1,572

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Preface Hypoxia inducible factors (HIFs) are broadly expressed in human cancers, and HIF1α and HIF2α were previously suspected of promoting tumor progression through largely overlapping functions. However, this relatively simple model has now been challenged in light of recent data from genome-wide analyses of human tumors, genetically engineered mouse models of cancer, and systems biology approaches that reveal unique and sometimes opposing HIFa activities in both normal physiology and disease. These effects are mediated in part through regulation of unique target genes, as well as direct and indirect interactions with important oncoproteins and tumor suppressors, including MYC and p53. As HIF inhibitors are currently under clinical evaluation as cancer therapeutics, a more thorough understanding of unique roles performed by HIF1α and HIF2α in human neoplasia is warranted. This Review summarizes our rapidly changing understanding of shared and independent HIF1α and HIF2α activities in tumor growth and progression, and the implications for using selective HIF inhibitors as cancer therapeutics.

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“…Both HIF-a subunits can bind to the endogenous HREs of hypoxiaresponsive genes; however, binding is not sufficient for target gene activation. 35,36 In contrast, C-terminal regions of each protein are required for specificity. For select targets, the N-TAD is sufficient to confer target gene specificity and replacement of the HIF-2a N-TAD with the analogous region of HIF-1a switches the specificity of these proteins.…”

Section: Transcriptional Targetsmentioning

confidence: 99%

“…36 In contrast, targets such as prolyl hydroxylase-3 (PHD3) require additional regions of the HIF-2a protein to be induced. 35 Cooperation with other transcription factors may also be required for maximal and cell-type-specific upregulation of HIF target genes ( Figure 2). Multiple Ets family transcription factors can cooperate with HIF-2a for hypoxic gene induction.…”

Section: Transcriptional Targetsmentioning

confidence: 99%

Biology of hypoxia-inducible factor-2α in development and disease

Patel¹,

Simon²

2008

Cell Death Differ

295

237

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The transcriptional response to hypoxia is primarily mediated by two hypoxia-inducible factors -HIF-1a and HIF-2a. While these proteins are highly homologous, increasing evidence suggests they have unique transcriptional targets and differential impact on tumor growth. Furthermore, non-transcriptional effects of the HIF-a subunits, including effects on the Notch and c-Myc pathways, contribute to their distinct functions. HIF-2a transcriptional targets include genes involved in erythropoiesis, angiogenesis, metastasis, and proliferation. Therefore, HIF-2a contributes significantly to both normal physiology as well as tumorigenesis. Here, we summarize the function of HIF-2a during development as well as its contribution to pathologic conditions, such as tumors and vascular disease. Cell Death and Differentiation (2008) Cells, tissues, and organisms experience reduced oxygen (O 2 ) tension, or 'hypoxia,' under both physiologic and pathologic conditions. 1 During the rapid cell proliferation associated with early embryonic development, physiologic hypoxia stimulates the development of the hematopoietic and circulatory systems. 2 Rapidly growing tumors also experience hypoxia due to insufficient and defective vascularization. 3 The hypoxia-inducible factors (HIFs) mediate the adaptive response to decreased O 2 availability at the cellular and organismal level. HIFs are heterodimeric proteins belonging to the basic helix-loop-helix (bHLH)/Per-ARNTSim (PAS) domain family of transcription factors. 4 Under normoxic conditions, the HIF-a subunits are hydroxylated on key proline residues, which allows for recognition by the von Hippel-Lindau (pVHL) tumor suppressor, the substrate recognition component of an E3 ubiquitin ligase complex that targets HIF-a for proteosomal degradation. [5][6][7][8][9] In hypoxic conditions, these hydroxylation events are inhibited allowing the a subunits to enter the nucleus and bind the stable subunit or aryl hydrocarbon receptor nuclear translocator (ARNT), forming a functional transcriptional complex. Among HIF transcriptional targets are genes involved in glycolysis, angiogenesis, erythropoiesis, cell death, and differentiation. 10

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Target gene selectivity of hypoxia-inducible factor-α in renal cancer cells is conveyed by post-DNA-binding mechanisms

Cited by 93 publications

References 35 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

HIF1α and HIF2α: sibling rivalry in hypoxic tumour growth and progression

Biology of hypoxia-inducible factor-2α in development and disease

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