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Melanoma antigen-11 inhibits the hypoxia-inducible factor prolyl hydroxylase 2 and activates hypoxic response.

ABSTRACT: Activation of hypoxia-inducible factors (HIF), responsible for tumor angiogenesis and glycolytic switch, is regulated by reduced oxygen availability. Normally, HIF-alpha proteins are maintained at low levels, controlled by site-specific hydroxylation carried out by HIF prolyl hydroxylases (PHD) and subsequent proteasomal degradation via the von Hippel-Lindau ubiquitin ligase. Using a yeast two-hybrid screen, we identified an interaction between melanoma antigen-11 (MAGE-11) cancer-testis antigen and the major HIF-alpha hydroxylating enzyme PHD2. The interaction was confirmed by a pull-down assay, coimmunoprecipitation, and colocalization in both normoxic and hypoxic conditions. Furthermore, MAGE-9, the closest homologue of MAGE-11, was also found to interact with PHD2. MAGE-11 inhibited PHD activity without affecting protein levels. This inhibition was accompanied by stabilization of ectopic or endogenous HIF-1alpha protein. Knockdown of MAGE-11 by small interfering RNA results in decreased hypoxic induction of HIF-1alpha and its target genes. Inhibition of PHD by MAGE-11, and following activation of HIFs, is a novel tumor-associated HIF regulatory mechanism. This finding provides new insights into the significance of MAGE expression in tumors and may provide valuable tools for therapeutic intervention because of the restricted expression of the MAGE gene family in cancers, but not in normal tissues.

SUBMITTER: Aprelikova O

PROVIDER: S-EPMC2629394 | biostudies-literature | 2009 Jan

REPOSITORIES: biostudies-literature

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Melanoma antigen-11 inhibits the hypoxia-inducible factor prolyl hydroxylase 2 and activates hypoxic response.

Aprelikova Olga O Pandolfi Silvia S Tackett Sean S Ferreira Mark M Salnikow Konstantin K Ward Yvona Y Risinger John I JI Barrett J Carl JC Niederhuber John J

Cancer research 20090101 2

Activation of hypoxia-inducible factors (HIF), responsible for tumor angiogenesis and glycolytic switch, is regulated by reduced oxygen availability. Normally, HIF-alpha proteins are maintained at low levels, controlled by site-specific hydroxylation carried out by HIF prolyl hydroxylases (PHD) and subsequent proteasomal degradation via the von Hippel-Lindau ubiquitin ligase. Using a yeast two-hybrid screen, we identified an interaction between melanoma antigen-11 (MAGE-11) cancer-testis antigen ...[more]

PMID: 19147576

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Project description:BackgroundThe endothelin B receptor (ET(B)R) promotes tumorigenesis and melanoma progression through activation by endothelin (ET)-1, thus representing a promising therapeutic target. The stability of hypoxia-inducible factor (HIF)-1alpha is essential for melanomagenesis and progression, and is controlled by site-specific hydroxylation carried out by HIF-prolyl hydroxylase domain (PHD) and subsequent proteosomal degradation.Principal findingsHere we found that in melanoma cells ET-1, ET-2, and ET-3 through ET(B)R, enhance the expression and activity of HIF-1alpha and HIF-2alpha that in turn regulate the expression of vascular endothelial growth factor (VEGF) in response to ETs or hypoxia. Under normoxic conditions, ET-1 controls HIF-alpha stability by inhibiting its degradation, as determined by impaired degradation of a reporter gene containing the HIF-1alpha oxygen-dependent degradation domain encompassing the PHD-targeted prolines. In particular, ETs through ET(B)R markedly decrease PHD2 mRNA and protein levels and promoter activity. In addition, activation of phosphatidylinositol 3-kinase (PI3K)-dependent integrin linked kinase (ILK)-AKT-mammalian target of rapamycin (mTOR) pathway is required for ET(B)R-mediated PHD2 inhibition, HIF-1alpha, HIF-2alpha, and VEGF expression. At functional level, PHD2 knockdown does not further increase ETs-induced in vitro tube formation of endothelial cells and melanoma cell invasiveness, demonstrating that these processes are regulated in a PHD2-dependent manner. In human primary and metastatic melanoma tissues as well as in cell lines, that express high levels of HIF-1alpha, ET(B)R expression is associated with low PHD2 levels. In melanoma xenografts, ET(B)R blockade by ET(B)R antagonist results in a concomitant reduction of tumor growth, angiogenesis, HIF-1alpha, and HIF-2alpha expression, and an increase in PHD2 levels.ConclusionsIn this study we identified the underlying mechanism by which ET-1, through the regulation of PHD2, controls HIF-1alpha stability and thereby regulates angiogenesis and melanoma cell invasion. These results further indicate that targeting ET(B)R may represent a potential therapeutic treatment of melanoma by impairing HIF-1alpha stability.

Dataset Information

Melanoma antigen-11 inhibits the hypoxia-inducible factor prolyl hydroxylase 2 and activates hypoxic response.

Publications

Melanoma antigen-11 inhibits the hypoxia-inducible factor prolyl hydroxylase 2 and activates hypoxic response.

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