Ji-Won Lee^1*, Seong-Hui Bae^1* Joo-Won Jeong¹, Se-Hee Kim¹ and Kyu-Won Kim^1,2

¹Research Institute of Pharmaceutical Sciences and College of Pharmacy, Seoul National University Seoul 151-742, Korea
²Corresponding author: Tel, 82-2-880-6988; Fax, 82-2-872-1795;
*These authors contributed equally to this work.

Abbreviations: 17-AAG, 17-allyl-aminogel-danamycin; ARNT, aryl hydrocarbon receptor nuclear translocator; EGFR, epidermal growth factor receptor; EPAS1, endothelial PAS domain protein 1; FIH-1, factor inhibiting HIF-1; HDAC, histone deacetylase; HIF-1, hypoxia-inducible factor; HRE, hypoxia response element;
HSP 90, molecular chaperon heat shock protein 90; IGF2, insulin like growth factor-2; IGFIR, insulin-like growth factor 1 receptor; IPAS, inhibitory PAS domain protein; MAPK, mitogen-activated protein kinase; MEK, MAP/ERK kinase; NAT, N-acetyltransferase; NO, Nitric oxide; ODD domain, oxygen-dependent degradation domain; PHD, prolyl hydroxylase; PI3K, phosphatidylinositol 3-kinase; PMA, phorbol-12-myristate-13-acetate; TAD-C, C-terminal transactivation domains; TAD-N, N-terminal transactivation domains; TGF- α, transforming growth factor-α; VEGF, vascular endothelial cell growth factor

Abstract

Hypoxia-inducible factor (HIF-1) is an oxygen-dependent transcriptional activator, which plays crucial roles in the angiogenesis of tumors and mammalian development. HIF-1 consists of a constitutively expressed HIF-1β subunit and one of three subunits (HIF-1α, HIF-2α or HIF-3α). The stability and activity of HIF-1α are regulated by various post-translational modifications, hydroxylation, acetylation, and phosphorylation. Therefore, HIF-1α interacts with several protein factors including PHD, pVHL, ARD-1, and p300/CBP. Under normoxia, the HIF-1α subunit is rapidly degraded via the von Hippel- Lindau tumor suppressor gene product  (pVHL)- mediated ubiquitin-proteasome pathway. The association of pVHL and HIF-1α 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, in the hypoxia condition, HIF-1α subunit becomes stable and interacts with coactivators such as p300/CBP to modulate its transcriptional activity. Eventually, HIF-1 acts as a master regulator of numerous hypoxia- inducible genes under hypoxic conditions. The target genes of HIF-1 are especially related to angiogenesis, cell proliferation/survival, and glucose/ iron metabolism. Moreover, it was reported that the activation of HIF-1α is closely associated with a variety of tumors and oncogenic pathways.
Hence, the blocking of HIF-1α itself or HIF-1α interacting proteins inhibit tumor growth. Based on these findings, HIF-1 can be a prime target for anticancer therapies. This review summarizes the molecular mechanism of HIF-1α stability, the biological functions of HIF-1 and its potential applications of cancer therapies.

Keywords: ARD1; angiogenesis; anticancer therapy; cell proliferation/survival; HIF-1; glucose metabolismi; PHD; pVHL; p300/CBP; iron metabolism; transcription factor