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

Hypoxia-inducible factor 1 (HIF1) is up-regulated in most malignant tumors usually via interruption of ubiquitination and proteasomal degradation of its subunit alpha. Recently, we have shown that the principal ERV oncoprotein, latent membrane protein 1 (LMP1), activates HIF1 alpha and subsequently expression of HIFI-responsive genes in epithelial cells. Here, we explore the mechanism for HIF1 alpha 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 HIF1 alpha for degradation. As a result, LMP1 prevents formation of von Hippel-Lindau/HIF1 alpha complex, as shown by coimmunoprecipitation analyses. Thus, Siah1 is implicated in the regulation of HIF1 alpha and is involved in a recently appreciated aspect of ERV-mediated tumorigenesis, namely, the angiogenesis process triggered by LMP1.