The roles and signaling pathways of prolyl-4-hydroxylase 2 in the tumor microenvironment

Tumor hypoxia is a well-known microenvironmental factor that causes cancer progression and resistance to cancer treatment. Proline hydroxylases (PHDs), a small protein family, belong to an evolutionarily conserved superfamily of dioxygenases, considered the central regulator of the molecular hypoxia response. Prolyl-4-hydroxylase 2 (PHD2), one member of PHDs family, regulates the stability of the hypoxia-inducible factor-1 alpha (HIF-1 alpha) in response to oxygen availability. During hypoxia, the inhibition of PHD2 permits the accumulation of HIF-1 alpha, allowing the cellular adaptation to oxygen limitation, causing activation of numerous genes, which enhances the angiogenesis, metastasis and invasiveness. Accurate regulation of oxygen homeostasis is essential, and which implies PHD2 may have a regulatory role in the pathogenesis of cancer. Although ample evidence exists for a positive correlation between HIFs and tumor formation, metastasis and poor prognosis, the function of the PHD2 in carcinogenesis is less well understood. Despite their original role as the oxygen sensors of the cell and many of the its functions are clearly conveyed through the HIF system, PHD2 is currently known to display HIF-independent and hydroxylase-independent functions in cancer cells and stroma in the control of different cellular pathways. In this review, we summarize the recent advances in the structure, regulation and functions of PHD2 in cancer microenvironment.