Molecule Information

General Information of the Molecule (ID: Mol04437)

• Name: Egl nine homolog 1 (EGLN1) ,Homo sapiens
• Synonyms: Hypoxia-inducible factor prolyl hydroxylase 2; Prolyl hydroxylase domain-containing protein 2; SM-20
• Molecule Type: Protein
• Gene Name: EGLN1
• Gene ID: 54583
• Sequence:
  MANDSGGPGGPSPSERDRQYCELCGKMENLLRCSRCRSSFYCCKEHQRQDWKKHKLVCQG
  SEGALGHGVGPHQHSGPAPPAAVPPPRAGAREPRKAAARRDNASGDAAKGKVKAKPPAD
  P AAAASPCRAAAGGQGSAVAAEAEPGKEEPPARSSLFQEKANLYPPSNTPGDALSPGGG
  LR PNGQTKPLPALKLALEYIVPCMNKHGICVVDDFLGKETGQQIGDEVRALHDTGKFTD
  GQL VSQKSDSSKDIRGDKITWIEGKEPGCETIGLLMSSMDDLIRHCNGKLGSYKINGRT
  KAMV ACYPGNGTGYVRHVDNPNGDGRCVTCIYYLNKDWDAKVSGGILRIFPEGKAQFAD
  IEPKF DRLLFFWSDRRNPHEVQPAYATRYAITVWYFDADERARAKVKYLTGEKGVRVEL
  NKPSDS VGKDVF
• Function: Cellular oxygen sensor that catalyzes, under normoxicconditions, the post-translational formation of 4-hydroxyproline inhypoxia-inducible factor alpha proteins. Hydroxylates a specificproline found in each of the oxygen-dependent degradation domains of HIF1A. Also hydroxylatesHIF2A. Has a preference for the CODD site for both HIF1A and HIF1B.Hydroxylated HIFs are then targeted for proteasomal degradation via thevon Hippel-Lindau ubiquitination complex. Under hypoxic conditions, thehydroxylation reaction is attenuated allowing HIFs to escapedegradation resulting in their translocation to the nucleus,heterodimerization with HIF1B, and increased expression of hypoxy-inducible genes. EGLN1 is the most important isozyme under normoxiaand, through regulating the stability of HIF1, involved in varioushypoxia-influenced processes such as angiogenesis in retinal andcardiac functionality. Target proteins are preferentially recognizedvia a LXXLAP motif. {ECO:0000269|PubMed:11595184,ECO:0000269|PubMed:12181324, ECO:0000269|PubMed:12351678,ECO:0000269|PubMed:15897452, ECO:0000269|PubMed:19339211,ECO:0000269|PubMed:21792862, ECO:0000269|PubMed:25129147}.
• Uniprot ID: EGLN1_HUMAN
• Ensembl ID: ENSG000001357669
• HGNC ID: HGNC:1232

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 1 drug(s) in total

Gemcitabine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Bladder cancer [ICD-11: 2C94.0] [1]

• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• Resistant Drug: Gemcitabine
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: HIF1alpha stabilization signaling pathway; Regulation; N.A.
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: J82 cells; Bladder; Homo sapiens (Human); CVCL_0359
• In Vivo Model: BALB/c female nude mice model; Mus musculus
• Experiment for Molecule Alteration: MS analysis; Western blot assay; Immunohistochemistry
• Experiment for Drug Resistance: IC50 assay; Cell proliferation assay; Migration ability assay; Invasion ability assay; Apoptosis assay
• Mechanism Description: Metabolomics analyses in our lab's gemcitabine- and cisplatin-resistant cell lines revealed increased phosphoglycerate dehydrogenase (PHGDH) expression in gemcitabine-resistant cells compared with parental cells. Isocitrate dehydrogenase 2 (IDH2) gain of function stabilized hypoxia-inducible factor1alpha (HIF1alpha) expression, stimulating aerobic glycolysis. In gemcitabine-resistant cells, elevated fumaric acid suppressed prolyl hydroxylase domain-containing protein 2/Egl nine homolog 1 (PHD2) and stabilized HIF1alpha expression. PHGDH downregulation or inhibition in gemcitabine-resistant BC cells inhibited their proliferation, migration, and invasion.

References

• Ref 1: Targeting metabolic reprogramming to overcome drug resistance in advanced bladder cancer: insights from gemcitabine- and cisplatin-resistant models. Mol Oncol. 2024 Sep;18(9):2196-2211.