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Melanoma Antigen-11 Inhibits the Hypoxia-Inducible Factor Prolyl Hydroxylase 2 and Activates Hypoxic Response

¹ Laboratory of Tumor and Stem Cell Biology, ² Laboratory of Biosystems and Cancer, and ³ Laboratory of Comparative Carcinogenesis, National Cancer Institute, Bethesda, Maryland and ⁴ Curtis and Elizabeth Anderson Cancer Institute at Memorial Health University Medical Center, Savannah, Georgia

Requests for reprints: Olga Aprelikova, National Cancer Institute, Building 37, Room 1042, 9000 Rockville Pike, Bethesda, MD 20892. Phone: 301-435-5774; Fax: 301-435-8666; E-mail: apreliko{at}mail.nih.gov.

Key Words: HIF • hypoxia • MAGE-11 • PHD2

Activation of hypoxia-inducible factors (HIF), responsible for tumor angiogenesis and glycolytic switch, is regulated by reduced oxygen availability. Normally, HIF- 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- 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-1 protein. Knockdown of MAGE-11 by small interfering RNA results in decreased hypoxic induction of HIF-1 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. [Cancer Res 2009;69(2):616–24]

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