HIF-1alpha: a Valid Therapeutic Target for Tumor Therapy.
- Author:
Soon Sun HONG
1
;
Hyunseung LEE
;
Kyu Won KIM
Author Information
1. Research Institute of Pharmaceutical Sciences and College of Pharmacy, Seoul National University, Seoul 151-742, Korea. qwonkim@plaza.snu.ac.kr
- Publication Type:Review
- Keywords:
ARD1;
Angiogenesis;
Anticancer therapy;
Cell proliferation/survival;
Glucose metabolism;
HIF-1;
Iron metabolism;
PHD;
SUMO;
pVHL;
p300/CBP;
Transcription factor
- MeSH:
Acetylation;
Anoxia;
Cell Proliferation;
Genes, Tumor Suppressor;
Glucose;
Hydroxylation;
Iron;
Lysine;
Metabolism;
Oxygen;
Phosphorylation;
Protein Processing, Post-Translational;
Transcription Factors
- From:Cancer Research and Treatment
2004;36(6):343-353
- CountryRepublic of Korea
- Language:English
-
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.
