The role of hypoxia-inducible factors in tumorigenesis

Abstract

Hypoxia-inducible factors (HIFs) are essential mediators of the cellular oxygen-signaling pathway. They are heterodimeric transcription factors consisting of an oxygen-sensitive alpha subunit (HIF-alpha) and a constitutive beta subunit (HIF-beta) that facilitate both oxygen delivery and adaptation to oxygen deprivation by regulating the expression of genes that control glucose uptake, metabolism, angiogenesis, erythropoiesis, cell proliferation, and apoptosis. In most experimental models, the HIF pathway is a positive regulator of tumor growth as its inhibition often results in tumor suppression. In clinical samples, HIF is found elevated and correlates with poor patient prognosis in a variety of cancers. In summary, HIF regulates multiple aspects of tumorigenesis, including angiogenesis, proliferation, metabolism, metastasis, differentiation, and response to radiation therapy, making it a critical regulator of the malignant phenotype.

Figure 1

Schematic representation of HIF family member protein domains. HIFs are members of the basic helix-loop-helix (bHLH)/PER-ARNT-SIM (PAS) domain family of transcription factors that mediate transcriptional responses to oxygen deprivation. They bind to DNA as heterodimers composed of an oxygen-sensitive HIF-α subunit (HIF-1α, -2α, or -3α) and a constitutive HIF-β subunit (ARNT-1 and -2). The bHLH and PAS domains found in all HIF family members mediate DNA binding and dimerization, respectively. HIF-α subunits contain a unique oxygen-dependent degradation domain (ODD) that controls HIF-α stability in an oxygen-dependent manner. In addition, HIF family members contain transactivation domains (TADs) that mediate target gene activation. HIF-1α and HIF-2α contain two TADs that contribute to target gene activation

Figure 2

Mechanisms of HIF activation in cancer. Hypoxia is a common mechanism of HIF activation in cancer. Low oxygen tensions inhibit both prolyl-4-hydroxylase domain (PHD) and factor inhibiting HIF-1 (FIH-1) activity, which negatively regulates HIF stability and cofactor (p300/CBP) recruitment, respectively. Under normoxic conditions, PHD enzymes (PHD 1–3) utilize oxygen as a substrate to hydroxylate key proline residues located within the HIF-α ODD domain. This hydroxylation event mediates pVHL binding and subsequent ubiquitination and degradation by the 26S proteasome. Under conditions of hypoxia or loss of pVHL, HIF-α is stabilized and translocates to the nucleus where it heterodimerizes with ARNT and binds to hypoxia response elements (HREs) within regulatory regions of target genes. The HIF heterodimer activates gene expression at these sites upon cofactor (p300/CBP) recruitment. The interaction between HIF and p300 is regulated in an oxygen-dependent manner by FIH. FIH uses oxygen to hydroxylate asparagine residues within the HIF-α C-terminal transactivation domain, thereby preventing p300 binding. HIF activity can also be induced in tumor cells through activation of the PI-3 kinase/Akt-signaling pathway. Growth factor signaling, oncogenic Ras activation, or inhibition of negative regulators, including PTEN and TSC2 can activate the PI-3 kinase/Akt pathway and induce HIF activity in tumor cells

Figure 3

List of HIF-regulated genes that promote key aspects of tumorigenesis. HIF regulates the expression of over 100 genes that regulate key aspects of tumorigenesis, including angiogenesis, metabolism, proliferation, invasion, and metastasis. ALDA, aldolase A; ANG-1, angiopoietin 1; ANG-2, angiopoietin 2; CCND1, cyclin D1; CTGF, connective tissue growth factor; CXCR4, C-X-C chemokine receptor type 4; E-cadherin; EPO, erythropoietin; ENO1, enolase 1; FLT-1, VEGF receptor 1; FLK-1, VEGF receptor 2; GLUT-1, glucose transporter-1; GLUT-3, glucose transporter-3; HK1, hexokinase 1; HK2, hekokinase 2; IGF-2, insulin growth factor-2; IGF-BP2, IGF-factor-binding protein 2; LDHA, lactate dehydrogenase A; LOX, lysyl oxidase; MMP-2, matrix metalloproteinase-2; MMP-9, matrix metalloproteinase-9; MXI-1, max interactor 1; PAI-1, plasminogen activator inhibitor-1; PDGF-B, platelet-derived growth factor-B; PDK1, pyruvate dehydrogenase kinase 1; PFKL, phosphofructokinase L; PGK1, phosphoglycerate kinase 1; SDF-1, stromal-derived factor 1; TGF-α, transforming growth factor-α; TIE-2; UPAR, urokinase plasminogen activator receptor; VEGF, vascular endothelial growth factor