EBV Latent Membrane Protein 1 Up-regulates Hypoxia-Inducible Factor 1α through Siah1-Mediated Down-regulation of Prolyl Hydroxylases 1 and 3 in Nasopharyngeal Epithelial Cells

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Abstract
Hypoxia-inducible factor 1 (HIF1) is up-regulated in most malignant tumors usually via interruption of ubiquitination and proteasomal degradation of its subunit α. Recently, we have shown that the principal EBV oncoprotein, latent membrane protein 1 (LMP1), activates HIF1α and subsequently expression of HIF1-responsive genes in epithelial cells. Here, we explore the mechanism for HIF1α activation by LMP1 in nasopharyngeal epithelial cells: LMP1 up-regulates the level of Siah1 E3 ubiquitin ligase by enhancing its stability, which subsequently induces proteasomal degradation of prolyl HIF-hydroxylases 1 and 3 that normally mark HIF1α for degradation. As a result, LMP1 prevents formation of von Hippel-Lindau/HIF1α complex, as shown by coimmunoprecipitation analyses. Thus, Siah1 is implicated in the regulation of HIF1α and is involved in a recently appreciated aspect of EBV-mediated tumorigenesis, namely, the angiogenesis process triggered by LMP1. (Cancer Res 2006; 66(20): 9870-7)

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