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

Abstract

Hypoxia-inducible factor 1 (HIF1) is up-regulated in most malignant tumors usually via interruption of ubiquitination and proteasomal degradation of its subunit A. Recently, we have shown that the principal EBV oncoprotein, latent membrane protein 1 (LMP1), activates HIF1A and subsequently expression of HIF1-responsive genes in epithelial cells. Here, we explore the mechanism for HIF1A 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 HIF1A for degradation. As a result, LMP1 prevents formation of von Hippel-Lindau/HIF1A complex, as shown by coimmunoprecipitation analyses. Thus, Siah1 is implicated in the regulation of HIF1A 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)

Expression of seven-in-absentia homologue 1 and hypoxia-inducible factor 1 alpha: Novel prognostic factors of nasopharyngeal carcinoma

“…Recently, we demonstrated that Epstein-Barr virus (EBV)-associated latent membrane protein 1 (LMP1) increased the expression of HIF1α via the induction of Siah1 in human nasopharyngeal epithelial cells [16]. Moreover, EBV is closely related to the carcinogenesis of NPC [1].…”

Epstein-Barr Virus Latent Membrane Protein 1 is not Associated with Vessel Density nor with Hypoxia Inducible Factor 1 Alpha Expression in Nasopharyngeal Carcinoma Tissue

“…Prior studies showed that LMP1 transfection of lymphoblastoid and carcinoma cell lines induced HIF-1a in vitro [14,15]. If the same pathway were active in vivo, it might compel clinical trials of newly available antiangiogenic agents to thwart the effects of LMP1.…”

“…Compared to in vitro models in which LMP1 induced HIF-1a [14,15], in vivo settings can be expected to behave in a much more complicated fashion. Levels of host genes are influenced, at least in part, by the local tumor environment including oxygenation status, which is a potent regulator of HIF stabilization.…”

“…A relation between LMP1 expression and increased HIF-1a expression was found by Wakisaka et al [14] in both lymphoblastoid and epithelial cell lines. Subsequently Kondo et al [15] showed the mechanism by which LMP1 functions-it stabilizes SIAH1, an E3 ubiquitin ligase, which in turn ubiquitinates and destabilizes prolyl hydroxylase proteins (PHD1 and PHD3) that, under normoxic conditions, are responsible for hydroxylation and subsequent degradation of HIF-1a. In this manner, LMP1 expression effectively increases HIF-1a levels leading to downstream transcription of angiogenic factors.…”

Hypoxia inducible factor (HIF) function in innate immunity and infection

“…Recent co-immunoprecipation studies indicate EBV LMP1 enhances the stability of Siah1 E3 ubiquitin ligase, inducing proteasomal degradation of PHD-1 and PHD-3 that normally tag HIF-1α for degradation. LMP1 thus prevents formation of the VHL/HIF-1α complex, providing a mechanism for HIF-1α stabilization during EBV nasopharyngeal cell infection [44].…”