The EGLN-HIF O-Sensing System: Multiple Inputs and Feedbacks

Overview

Journal Mol Cell

Publisher Cell Press

Specialty Cell Biology

Date 2017 Jun 17

PMID 28622522

Citations 132

Authors

Mircea Ivan

William G Kaelin Jr

Affiliations

Soon will be listed here.

Abstract

The EGLN (also called PHD) prolyl hydroxylase enzymes and their canonical targets, the HIFα subunits, represent the core of an ancient oxygen-monitoring machinery used by metazoans. In this review, we highlight recent progress in understanding the overlapping versus specific roles of EGLN enzymes and HIF isoforms and discuss how feedback loops based on recently identified noncoding RNAs introduce additional layers of complexity to the hypoxic response. Based on novel interactions identified upstream and downstream of EGLNs, an integrated network connecting oxygen-sensing functions to metabolic and signaling pathways is gradually emerging with broad therapeutic implications.

Citing Articles

Genetic Markers of Postmortem Brain Iron.

Cornelis M, Fazlollahi A, Bennett D, Schneider J, Ayton S J Neurochem. 2025; 169(2):e16309.

PMID: 39918201 PMC: 11804167. DOI: 10.1111/jnc.16309.

Oncogenic TFE3 fusions drive OXPHOS and confer metabolic vulnerabilities in translocation renal cell carcinoma.

Li J, Huang K, Thakur M, McBride F, Sadagopan A, Gallant D Nat Metab. 2025; .

PMID: 39915638 DOI: 10.1038/s42255-025-01218-9.

Ferroptosis and its relationship with cancer.

Su C, Xue Y, Fan S, Sun X, Si Q, Gu Z Front Cell Dev Biol. 2025; 12:1423869.

PMID: 39877159 PMC: 11772186. DOI: 10.3389/fcell.2024.1423869.

Non-canonical Function of Prolyl Hydroxylase Domain 2 in Breast Cancer Cell Growth and Progression: Role of Peptidyl-prolyl Cis-trans Isomerase NIMA-interacting 1.

Guillen-Quispe Y, Kim S, Saeidi S, Choi G, Chelakkot C, Zhou T J Cancer Prev. 2025; 29(4):129-139.

PMID: 39790223 PMC: 11706723. DOI: 10.15430/JCP.24.031.

Gene expression and DNA methylation changes in response to hypoxia in toxicant-adapted Atlantic killifish (Fundulus heteroclitus).

Aluru N, Venkataraman Y, Murray C, DePascuale V Biol Open. 2025; 14(1.

PMID: 39760289 PMC: 11744052. DOI: 10.1242/bio.061801.

References

Mazumdar J, Hickey M, Pant D, Durham A, Sweet-Cordero A, Vachani A . HIF-2alpha deletion promotes Kras-driven lung tumor development. Proc Natl Acad Sci U S A. 2010; 107(32):14182-7. PMC: 2922515. DOI: 10.1073/pnas.1001296107. View

Dang C, Kim J, Gao P, Yustein J . The interplay between MYC and HIF in cancer. Nat Rev Cancer. 2007; 8(1):51-6. DOI: 10.1038/nrc2274. View

Koivunen P, Tiainen P, Hyvarinen J, Williams K, Sormunen R, Klaus S . An endoplasmic reticulum transmembrane prolyl 4-hydroxylase is induced by hypoxia and acts on hypoxia-inducible factor alpha. J Biol Chem. 2007; 282(42):30544-52. DOI: 10.1074/jbc.M704988200. View

Guo J, Chakraborty A, Liu P, Gan W, Zheng X, Inuzuka H . pVHL suppresses kinase activity of Akt in a proline-hydroxylation-dependent manner. Science. 2016; 353(6302):929-32. PMC: 5326551. DOI: 10.1126/science.aad5755. View

Xu W, Yang H, Liu Y, Yang Y, Wang P, Kim S . Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases. Cancer Cell. 2011; 19(1):17-30. PMC: 3229304. DOI: 10.1016/j.ccr.2010.12.014. View

German N, Yoon H, Yusuf R, Murphy J, Finley L, Laurent G . PHD3 Loss in Cancer Enables Metabolic Reliance on Fatty Acid Oxidation via Deactivation of ACC2. Mol Cell. 2016; 63(6):1006-20. PMC: 5040345. DOI: 10.1016/j.molcel.2016.08.014. View

Jaakkola P, Mole D, Tian Y, Wilson M, Gielbert J, Gaskell S . Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science. 2001; 292(5516):468-72. DOI: 10.1126/science.1059796. View

Lee D, Sohn H, Park Z, Oh S, Kang Y, Lee K . A lactate-induced response to hypoxia. Cell. 2015; 161(3):595-609. DOI: 10.1016/j.cell.2015.03.011. View

Nadtochiy S, Schafer X, Fu D, Nehrke K, Munger J, Brookes P . Acidic pH Is a Metabolic Switch for 2-Hydroxyglutarate Generation and Signaling. J Biol Chem. 2016; 291(38):20188-97. PMC: 5025701. DOI: 10.1074/jbc.M116.738799. View

10.

Bigham A, Lee F . Human high-altitude adaptation: forward genetics meets the HIF pathway. Genes Dev. 2014; 28(20):2189-204. PMC: 4201282. DOI: 10.1101/gad.250167.114. View

11.

Scheuermann T, Tomchick D, Machius M, Guo Y, Bruick R, Gardner K . Artificial ligand binding within the HIF2alpha PAS-B domain of the HIF2 transcription factor. Proc Natl Acad Sci U S A. 2009; 106(2):450-5. PMC: 2626723. DOI: 10.1073/pnas.0808092106. View

12.

Flashman E, Davies S, Yeoh K, Schofield C . Investigating the dependence of the hypoxia-inducible factor hydroxylases (factor inhibiting HIF and prolyl hydroxylase domain 2) on ascorbate and other reducing agents. Biochem J. 2010; 427(1):135-42. DOI: 10.1042/BJ20091609. View

13.

Yang M, Chowdhury R, Ge W, Hamed R, McDonough M, Claridge T . Factor-inhibiting hypoxia-inducible factor (FIH) catalyses the post-translational hydroxylation of histidinyl residues within ankyrin repeat domains. FEBS J. 2011; 278(7):1086-97. PMC: 3569879. DOI: 10.1111/j.1742-4658.2011.08022.x. View

14.

Semenza G . Hypoxia-inducible factors in physiology and medicine. Cell. 2012; 148(3):399-408. PMC: 3437543. DOI: 10.1016/j.cell.2012.01.021. View

15.

Kim J, Tchernyshyov I, Semenza G, Dang C . HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab. 2006; 3(3):177-85. DOI: 10.1016/j.cmet.2006.02.002. View

16.

Bruick R, McKnight S . A conserved family of prolyl-4-hydroxylases that modify HIF. Science. 2001; 294(5545):1337-40. DOI: 10.1126/science.1066373. View

17.

Zheng X, Zhai B, Koivunen P, Shin S, Lu G, Liu J . Prolyl hydroxylation by EglN2 destabilizes FOXO3a by blocking its interaction with the USP9x deubiquitinase. Genes Dev. 2014; 28(13):1429-44. PMC: 4083087. DOI: 10.1101/gad.242131.114. View

18.

Coleman M, McDonough M, Hewitson K, Coles C, Mecinovic J, Edelmann M . Asparaginyl hydroxylation of the Notch ankyrin repeat domain by factor inhibiting hypoxia-inducible factor. J Biol Chem. 2007; 282(33):24027-38. DOI: 10.1074/jbc.M704102200. View

19.

Ivan M, Kondo K, Yang H, Kim W, Valiando J, Ohh M . HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science. 2001; 292(5516):464-8. DOI: 10.1126/science.1059817. View

20.

Favaro E, Ramachandran A, McCormick R, Gee H, Blancher C, Crosby M . MicroRNA-210 regulates mitochondrial free radical response to hypoxia and krebs cycle in cancer cells by targeting iron sulfur cluster protein ISCU. PLoS One. 2010; 5(4):e10345. PMC: 2859946. DOI: 10.1371/journal.pone.0010345. View