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The multifaceted role of EGLN family prolyl hydroxylases in cancer: going beyond HIF regulation

Abstract

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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Fig. 1: Oxygen-dependent HIF regulation.
Fig. 2: EGLN proteins domains and post-translational modifications.
Fig. 3: Overview of mechanisms regulating EGLNs.
Fig. 4: Overview of the intracellular pathways modulated by EGLN enzymes.
Fig. 5: Different roles of EGLN isoforms in different cancer types.
Fig. 6: EGLN1 role in the tumor microenvironment.

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Acknowledgements

The research leading to this work has received funding from AIRC under IG 2021 - ID. 26377 project – P.I. Sancisi Valentina. Valentina Sancisi is funded by the Italian Ministry of Health through Bando per la Valorizzazione della Ricerca in ambito oncologico 2020 – Fondi 5 per Mille 2018. Giulia Gobbi is funded by the Italian Ministry of Health through Bando per la Valorizzazione della Ricerca in ambito oncologico 2019 – Fondi 5 per Mille 2017. Francesca Reggiani is supported by Fondazione Umberto Veronesi (FUV). This study was partially supported by Italian Ministry of Health – Ricerca Corrente Annual Program 2023.

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Conceptualization: VS and SS; literature review: SS, GG, FR, and VS; Writing and revising the paper: SS, GG, FR, AC, and VS.

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Strocchi, S., Reggiani, F., Gobbi, G. et al. The multifaceted role of EGLN family prolyl hydroxylases in cancer: going beyond HIF regulation. Oncogene 41, 3665–3679 (2022). https://doi.org/10.1038/s41388-022-02378-8

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