EGLN1 (PHD2) role in tumor microenvironment: insights for therapeutic targeting

Abstract

The tumor microenvironment (TME) is often hypoxic. EGLN1, which encodes the oxygen sensor PHD2, plays a crucial role not only in the survival of cancer cells but also in regulating other cell types that reside in the TME. In this Review, we explore the role of this protein in some of the key components of the TME, focusing on the functions of EGLN1/PHD2 in endothelial, stromal and immune cells. So far, the activity of EGLN1/PHD2 has been characterized in different cell types, albeit with controversial outcomes in different cancer settings. This Review aims to discuss the role of EGLN1/PHD2 in the TME and the strategies targeting this protein that might be used to hit tumors.

Fig. 1. Hypoxia response pathway.

In normoxia, the PHD enzyme hydroxylates the HIF-α subunit, leading to recognition by pVHL and degradation by the proteasome. In hypoxia, PHD enzyme is inactive and the HIF-α subunit is stabilized, enters the nucleus, dimerizes with HIF-β subunit and activates the transcription of hypoxic response genes. Created in https://BioRender.com.

Fig. 2. The multifaceted relationship among hypoxia, PHD enzymes and HIF factors in supporting or restraining tumor growth.

Hypoxia can regulate other enzymes of the 2-OGDD family, besides the PHDs and FIH. Different mechanisms can regulate the activity of the PHD enzymes, including the presence of binding partners, the metabolic status of the cell and specific post-translational modifications (PTM). The HIF proteins are the main targets of PHDs, but several alternative targets have been described, including p53, AKT1, BRD4 and DYRK1, holding the possibility to influence tumor behaviour. Finally, a number of pro-oncogenic signals have been shown to stabilize the HIF-α subunit in a oxygen-independent way. Created in https://BioRender.com.

Fig. 3. The relationship between hypoxia and angiogenesis in cancer.

a,b The hypoxic TME shapes blood vessels and induces vasculogenesis (a) to feed the tumor and potentially lead to metastasis (b). c Angiogenesis normalization may lead to hypoxia relief, anticancer drug delivery and immune surveillance reactivation. Created in https://BioRender.com.

Fig. 4. Effect of PHD inhibitors in CAFs.

PHD2 inhibition in CAFs induces their deactivation, resulting in TME matrix remodeling and reduced metastatic potential of cancer cells. Created in https://BioRender.com.

Fig. 5. The effects of PHD2 inactivation on macrophage function in cancer TME.

PHD2 genetic or pharmacological inhibition leads to metabolic reprogramming and increased phagocytic activity in TAMs. Created in https://BioRender.com.

Fig. 6. Effects of PHD2 inhibition in T lymphocytes.

PHD2 inactivation shifts CD8⁺ T cell metabolism, resulting in an increased tumor killing potential. Created in https://BioRender.com.

Fig. 7. Pharmacological approaches to the hypoxia pathway.

Several PHD enzymes inhibitors such as roxadustat, daprodustat and vadadustat have been developed for the treatment of anemia. Belzutifan is a small molecule specifically inhibiting the dimerization of HIF-2α with HIF-β. Inhibitors of the HIF transcriptional target VEGF have been used for more than 20 years for cancer treatment. Created in https://BioRender.com.