Prolyl Hydroxylases 2 and 3 Act in Gliomas as Protective Negative Feedback Regulators of Hypoxia-Inducible Factors

Abstract

Adaptive responses to hypoxia in tumors are transcriptionally regulated by the hypoxia inducible factors (HIF-1α/HIF-2α), which are tightly controlled by the HIF-prolyl hydroxylases (PHD). Hypoxia induces expression of the PHD2 and PHD3 proteins in tumors but the pathobiological significance of these events is uncertain. Here, we show that PHD2 and PHD3 induction acts within a negative feedback loop to limit the hypoxic HIF response. In glioblastomas, PHD2 and PHD3 are hypoxia-inducible in vitro and expressed in hypoxic areas of tumors in vivo. Comparison with other PHDs revealed distinct cytoplasmatic and nuclear localization patterns of PHD2 and PHD3. Gain and loss of function experiments defined PHD2 and PHD3 as HIF target genes that remained operative even at low oxygen concentrations. We found that increased PHD levels could compensate for reduced oxygen availability to regulate the HIF response. This negative feedback loop protected tumor cells against hypoxia-induced cell death, functionally implicating this pathway in the control of the tumor-suppressive components of the HIF system in glioblastoma. Moreover, PHD inhibition facilitated cell death induction by staurosporine or tumor necrosis factor-related apoptosis-inducing ligand, hinting at a more general protective role of PHD in the regulation of cell viability. In summary, our findings recognize the PHD/HIF regulatory axis as a novel therapeutic target to disable a tumor's ability to adjust to hypoxic conditions and control cell survival, helping to potentially overcome therapeutic cell death resistance in glioblastomas. Cancer Res; 70(1); 357-66. ©2010 AACR.

Maternal Undernutrition Induces the Expression of Hypoxia-Related Genes in the Fetal Brain

“…The symbol, name, relationship with mTOR and the respective references are provided in this table. al. 2002), is increased in hypoxic condition (Henze et al 2010). On the other hand, p53 expression was not increased in the L group.…”

Potential regulation of glioma through the induction of apoptosis signaling via Egl-9 family hypoxia-inducible factor 3

“…The Egln3 protein is unregulated in numerous types of human cancer, including pancreatic cancer (32) and glioblastoma (27). The function of Egln3 is dependent on prolyl hydroxylase activity through which it hydroxylates a number of targets, including Hif-2α (19) and other α subunits of Hif, larger subunits of RNA polymerase II, pyruvate kinase M2 and β2-adrenergic receptors (11,14,(33)(34)(35)(36).…”

“…The upregulation of Hif-2α is also associated with proapoptotic activity (22). However, the role of Egln hydroxylases in cancer biology is poorly understood, with two varying hypotheses currently presented; one suggesting that they function as tumor suppressors and the other favoring their contribution towards tumor aggressiveness (23)(24)(25)(26)(27)(28).…”

The HIF-2α-Driven Pseudo-Hypoxic Phenotype in Tumor Aggressiveness, Differentiation, and Vascularization

“…In further support of a role for Hif2a in sympathetic development, mice lacking the HIF prolyl hydroxylase PHD3 displayed an increased number (but reduced functionality) of sympathetic cells in the adrenal medulla, carotid body and the superior cervical ganglia due to reduced apoptosis (Bishop et al 2008). A reasonable assumption based on the role of PHD3 in targeting HIFs for degradation is that HIF protein levels in general would be higher in PHD3 -/-animals, and in vitro studies have suggested that PHD3 is more important in regulation of HIF-2α than HIF-1α (Appelhoff et al 2004;Henze et al 2009). Indeed, the sympathetic phenotype of Phd3 -/-mice was intriguingly reversed by crossing animals with heterozygous Hif2a +/-(but not Hif1a +/-) mice, again indicating that proper control of Hif2a expression is crucial for normal SNS development (Bishop et al 2008).…”