Cancer Res Treat.  2004 Dec;36(6):343-353.

HIF-1alpha: a Valid Therapeutic Target for Tumor Therapy

• Hong SS
• Lee H
• Kim KW

Abstract

Hypoxia plays a major role in the induction of angiogenesis during tumor development. One mechanism by which tumor cells respond to a reduced oxygen level is via the activation of hypoxia-inducible factor-1 (HIF-1). HIF-1 is an oxygen-dependent transcriptional activator that plays crucial roles in the angiogenesis of tumors and mammalian development. HIF-1 consists of a constitutively expressed HIF-1beta subunit and the highly regulated HIF-1 alpha subunits. The stability and activity of HIF-1alpha are regulated by various post-translational modifications, hydroxylation, acetylation, phosphorylation and sumoyaltion. Therefore, HIF-1alpha interacts with several protein factors including PHD, pVHL, ARD-1, SUMO and p300/ CBP. Under normoxia, the HIF-1alpha subunit is rapidly degraded via the von Hippel-Lindau tumor suppressor gene product (pVHL)-mediated ubiquitin/proteasome pathway. The association of pVHL and HIF-1alpha under normoxic conditions is triggered by the hydroxylation of prolines and the acetylation of lysine within a polypeptide segment known as the oxygen-dependent degradation (ODD) domain. On the contrary, under the hypoxia condition, the HIF-1alpha subunit becomes stable and interacts with coactivators such as p300/CBP to modulate its transcriptional activity. Under hypoxic conditions, HIF-1 eventually acts as a master regulator of numerous hypoxia-inducible genes. The target genes of HIF-1 are especially related to angiogenesis, cell proliferation and survival, and to glucose and iron metabolism. Moreover, it was reported that the activation of HIF-1alpha is closely associated with a variety of tumors and oncogenic pathways. Hence, the blocking of HIF-1alpha itself or the blocking of HIF-1alpha interacting proteins inhibits tumor growth. Based on these findings, HIF-1 can be a prime target for anticancer therapies. Therefore, this review summarizes the molecular mechanism of HIF-1alpha stability, the biological functions of HIF-1 and its potential applications for cancer therapies.

Keyword

ARD1; Angiogenesis; Anticancer therapy; Cell proliferation/survival; Glucose metabolism; HIF-1; Iron metabolism; PHD; SUMO; pVHL; p300/CBP; Transcription factor

MeSH Terms

Acetylation
Anoxia
Cell Proliferation
Genes, Tumor Suppressor
Glucose
Hydroxylation
Iron
Lysine
Metabolism
Oxygen
Phosphorylation
Protein Processing, Post-Translational
Transcription Factors
Glucose
Iron
Lysine
Oxygen
Transcription Factors

Figure

• 

  Fig. 1 Domain structures of HIF-1α and their potential function. HIF-1α possesses the basic helix-loop-helix (bHLH) and PER-ARNT-SIM (PAS) domains that are involved in dimerization with HIF-1β and DNA binding. Its C-terminal part contains two transacting domains (TAD) and an inhibitory domain (ID). The N-TAD lies within its ODD domain. The ODD domain regulates the stability of HIF-1α via recognition by the von Hippel-Lindau E3 ubiquitin ligase (pVHL).

• 

  Fig. 2 Splice variants of the HIF α subunit. bHLH: basic helix-loop-helix, PAS: Per/Arnt/Slim domain, ODD: oxygen dependent degradation domain, N-TAD: N-terminal transactivation domain, C-TAD: C-terminal transactivation domain, LZIP: leucine zipper.

• 

  Fig. 3 Target genes that are transcriptionally activated by HIF-1α1B-AR: α1B-adrenergic receptor, ADM: adrenomedullin, AK3: adenylate kinase 3, ALDA: aldolase A, ALDC: aldolase C, AMF: autocrine motility factor, CA9: Carbonic anhydrase 9, CATHD: cathepsin D, EG-VEGF: endocrine-gland-derived VEGF, ENG: endoglin, ET1: endothelin-1, ENO1: enolase 1, EPO: erythropoietin, FN1: fibronectin 1, GLUT1: glucose transporter 1, GLUT3: glucose transporter 3, GAPDH: glyceraldehyde-3-P-dehydrogenase, HK1: hexokinase 1, HK2: hexokinase 2, IGF2: insulin-like growth-factor 2, IGF-BP1: IGF-factor-binding-protein 1, IGF-BP2: IGF-factor-binding-protein 2, IGF-BP3: IGF-factor-binding-protein 3, ITF: intestinal trefoil factor, KRT14: keratin 14, KRT18: keratin 18, KRT19: keratin 19, LDHA: lactate dehydrogenase A, LEP: leptin, LRP1: LDL-receptor-related protein 1, MDR1: multidrug resistance 1, MMP2: matrix metalloproteinase 2, NOS2: nitric oxide synthase 2, PFKBF3: 6-phosphofructo-2-kinase/fructose-2:6-biphosphatase-3, PFKL: phosphor-fructo kinase L, PGK 1: phosphoglycerate kinase 1, PAI1: plasminogen-activator inhibitor 1, PKM: pyruvate kinase M, TGF-α: transforming growth factor-α, TGF-β3: transforming growth factor-β3, TPI: triosephosphate isomerase, VEGF: vascular endothelial growth factor, UPAR: urokinase plasminogen activator receptor, VEGFR2: VEGF receptor-2, VIM: vimentin.

• 

  Fig. 4 Molecular mechanism of HIF-1α stability. HIF-1α is subject to rapid degradation at normoxia by the pVHL-meditated ubiquitin-proteasome pathway, whereas hypoxia blocks degradation of HIF-1α leads to HIF-1α accumulation. HIF-1α hydroxylation on Pro402 and Pro564 and acetylation on Lys532 within the ODD domain facilitates binding with pVHL. As a result, HIF-1α is degraded via the ubiquitin-proteasome pathway. By contrast, sumoylation on Lys391 and Lys477 in the ODD domain may increase HIF-1α stability by competing with hydroxylation and acetylation for the pVHL binding.

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