EGLN1, EGLN2 and EGLN3 are proline hydroxylase whose main function is the regulation of the HIF factors. They work as oxygen sensors and are the main responsible of HIFα subunits degradation in normoxia. Being their activity strictly oxygen-dependent, when oxygen tension lowers, their control on HIFα is released, leading to activation of systemic and cellular response to hypoxia. However, EGLN family members activity is not limited to HIF modulation, but it includes the regulation of essential mechanisms for cell survival, cell cycle metabolism, proliferation and transcription. This is due to their reported hydroxylase activity on a number of non-HIF targets and sometimes to hydroxylase-independent functions. For these reasons, EGLN enzymes appear fundamental for development and progression of different cancer types, playing either a tumor-suppressive or a tumor-promoting role, according to EGLN isoform and to tumor context. Notably, EGLN1, the most studied isoform, has been shown to have also a central role in tumor micro-environment modulation, mediating CAF activation and impairing HIF1α -related angiogenesis, thus covering an important function in cancer metastasis promotion. Considering the recent knowledge acquired on EGLNs, the possibility to target these enzymes for cancer treatment is emerging. However, due to their multifaceted and controversial roles in different cancer types, the use of EGLN inhibitors as anti-cancer drugs should be carefully evaluated in each context.
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