Biological Role and Disease Relevance
PHD2 is the primary regulator of HIF-1α steady state levels in the cell. A PHD2 knockdown showed increased levels of HIF-1α under normoxia, and an increase in HIF-1α nuclear accumulation and HIF-dependent transcription. HIF-1α steady state accumulation was dependent on the amount of PHD silencing effected by siRNA in HeLa cells and a variety of other human cell lines.
However, although it would seem that PHD2 downregulates HIF-1α and thus also tumorigenesis, there have been suggestions of paradoxical roles of PHD2 in tumor proliferation. For example, one animal study showed tumor reduction in PHD2-deficient mice through activation of antiproliferative TGF-β signaling. Other in vivo models showed tumor-suppressing activity for PHD2 in pancreatic cancer as well as liver cancer. A study of 121 human patients revealed PHD2 as a strong prognostic marker in gastric cancer, with PHD2-negative patients having shortened survival compared to PHD2-positive patients.
As an additional point of interest, recent genome-wide association studies have suggested that EGLN1 may be involved in the low hematocrit phenotype exhibited by the Tibetan population and hence that EGLN1 may play a role in the heritable adaptation of this population to live at high altitude.
Read more about this topic: EGLN1
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