TISIDB

Summary
Symbol	EGLN3
Name	egl-9 family hypoxia-inducible factor 3
Aliases	PHD3; HIFPH3; HIF prolyl hydroxylase 3; EGL nine (C.elegans) homolog 3; egl nine homolog 3 (C. elegans); HIF ......
Chromosomal Location	14q12
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Basic function annotation. > Subcellular Location, Domain and Function > Gene Ontology > KEGG and Reactome Pathway

> Subcellular Location, Domain and Function [ TOP ]
Subcellular Location	Nucleus. Cytoplasm. Note=Colocalizes with WDR83 in the cytoplasm.
Domain	PF13640 2OG-Fe(II) oxygenase superfamily
Function	Cellular oxygen sensor that catalyzes, under normoxic conditions, the post-translational formation of 4-hydroxyproline in hypoxia-inducible factor (HIF) alpha proteins. Hydroxylates a specific proline found in each of the oxygen-dependent degradation (ODD) domains (N-terminal, NODD, and C-terminal, CODD) of HIF1A. Also hydroxylates HIF2A. Has a preference for the CODD site for both HIF1A and HIF2A. Hydroxylation on the NODD site by EGLN3 appears to require prior hydroxylation on the CODD site. Hydroxylated HIFs are then targeted for proteasomal degradation via the von Hippel-Lindau ubiquitination complex. Under hypoxic conditions, the hydroxylation reaction is attenuated allowing HIFs to escape degradation resulting in their translocation to the nucleus, heterodimerization with HIF1B, and increased expression of hypoxy-inducible genes. EGLN3 is the most important isozyme in limiting physiological activation of HIFs (particularly HIF2A) in hypoxia. Also hydroxylates PKM in hypoxia, limiting glycolysis. Under normoxia, hydroxylates and regulates the stability of ADRB2. Regulator of cardiomyocyte and neuronal apoptosis. In cardiomyocytes, inhibits the anti-apoptotic effect of BCL2 by disrupting the BAX-BCL2 complex. In neurons, has a NGF-induced proapoptotic effect, probably through regulating CASP3 activity. Also essential for hypoxic regulation of neutrophilic inflammation. Plays a crucial role in DNA damage response (DDR) by hydroxylating TELO2, promoting its interaction with ATR which is required for activation of the ATR/CHK1/p53 pathway. Target proteins are preferentially recognized via a LXXLAP motif.

> Gene Ontology [ TOP ]
Biological Process	GO:0001666 response to hypoxia GO:0006575 cellular modified amino acid metabolic process GO:0006919 activation of cysteine-type endopeptidase activity involved in apoptotic process GO:0010950 positive regulation of endopeptidase activity GO:0010952 positive regulation of peptidase activity GO:0018126 protein hydroxylation GO:0018208 peptidyl-proline modification GO:0018401 peptidyl-proline hydroxylation to 4-hydroxy-L-proline GO:0019471 4-hydroxyproline metabolic process GO:0019511 peptidyl-proline hydroxylation GO:0036293 response to decreased oxygen levels GO:0036294 cellular response to decreased oxygen levels GO:0043280 positive regulation of cysteine-type endopeptidase activity involved in apoptotic process GO:0043281 regulation of cysteine-type endopeptidase activity involved in apoptotic process GO:0043523 regulation of neuron apoptotic process GO:0043618 regulation of transcription from RNA polymerase II promoter in response to stress GO:0043620 regulation of DNA-templated transcription in response to stress GO:0045862 positive regulation of proteolysis GO:0051402 neuron apoptotic process GO:0052547 regulation of peptidase activity GO:0052548 regulation of endopeptidase activity GO:0061418 regulation of transcription from RNA polymerase II promoter in response to hypoxia GO:0070482 response to oxygen levels GO:0070997 neuron death GO:0071453 cellular response to oxygen levels GO:0071456 cellular response to hypoxia GO:1901214 regulation of neuron death GO:1901605 alpha-amino acid metabolic process GO:2000116 regulation of cysteine-type endopeptidase activity GO:2001056 positive regulation of cysteine-type endopeptidase activity
Molecular Function	GO:0005506 iron ion binding GO:0016705 oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen GO:0016706 oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, 2-oxoglutarate as one donor, and incorporation of one atom each of oxygen into both donors GO:0019842 vitamin binding GO:0031406 carboxylic acid binding GO:0031418 L-ascorbic acid binding GO:0031543 peptidyl-proline dioxygenase activity GO:0031545 peptidyl-proline 4-dioxygenase activity GO:0043168 anion binding GO:0051213 dioxygenase activity
Cellular Component	-

> KEGG and Reactome Pathway [ TOP ]
KEGG	hsa04066 HIF-1 signaling pathway
Reactome	R-HSA-2262749: Cellular response to hypoxia R-HSA-2262752: Cellular responses to stress R-HSA-1234176: Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha R-HSA-1234174: Regulation of Hypoxia-inducible Factor (HIF) by oxygen

Summary
Symbol	EGLN3
Name	egl-9 family hypoxia-inducible factor 3
Aliases	PHD3; HIFPH3; HIF prolyl hydroxylase 3; EGL nine (C.elegans) homolog 3; egl nine homolog 3 (C. elegans); HIF ......
Chromosomal Location	14q12
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Literatures that report relations between EGLN3 and anti-tumor immunity. The specific mechanism were also collected if the literature reports that a gene specifically promotes or inhibits the infiltration or function of T/NK cells.

> Text Mining

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Literatures describing the relation between EGLN3 and anti-tumor immunity in human cancer.

PMID	Cancer type	Relation to immunity	Evidence sentences
18980986	Renal Cell Carcinoma	Promote immunity	HIFPH3 was overexpressed in many RCC cell lines and primary RCC tissues, whereas it was not detectable in normal adult tissues by reverse transcription-PCR. Furthermore, HIFPH3-8 peptide-specific CTLs showed cytotoxicity against HIFPH3(+) RCC cell lines in a HLA-A24-restricted manner. HIFPH3 may be a target antigen in immunotherapy for RCC and HIFPH3-8 peptide could be used as a peptide vaccine for HLA-A*2402(+)/HIFPH3(+) RCC patients.

Summary
Symbol	EGLN3
Name	egl-9 family hypoxia-inducible factor 3
Aliases	PHD3; HIFPH3; HIF prolyl hydroxylase 3; EGL nine (C.elegans) homolog 3; egl nine homolog 3 (C. elegans); HIF ......
Chromosomal Location	14q12
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	High-throughput screening data (e.g. CRISPR-Cas9, shRNA and RNAi) for T cell-mediated killing. Genetic screen techniques can identify mechanisms of tumor cell resistance (e.g., PTPN2) and sensitivity (e.g., APLNR) to killing by cytotoxic T cells, the central effectors of anti-tumor immunity. After comprehensively searching, eight groups of screening data sets were collected in the current database. In this tab, users can check whether their selected genes cause resistance or increase sensitivity to T cell-mediated killing in various data sets.

> High-throughput Screening

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Statistical results of EGLN3 in screening data sets for detecting immune reponses.

PMID	Screening System	Cancer Type	Cell Line	Data Set	Statistical Results	Relation to immunity
29301958	CRISPR-Cas9	melanoma	B16F10	Pmel-1 T cell	NA/NS	NA/NS
29301958	CRISPR-Cas9	melanoma	B16F10	OT-1 T cell	NA/NS	NA/NS
28783722	CRISPR-Cas9	melanoma	Mel624	2CT-CRISPR	NA/NS	NA/NS
28723893	CRISPR-Cas9	melanoma	B16	GVAX+Anti-PD1	NA/NS	NA/NS
28723893	CRISPR-Cas9	melanoma	B16	GVAX	NA/NS	NA/NS
25691366	RNAi	Breast cancer	MCF7	Luc-CTL assay	NA/NS	NA/NS
24476824	shRNA	melanoma	B16	Primary screen	NA/NS	NA/NS
24476824	shRNA	melanoma	B16	Secondary screen	NA/NS	NA/NS

Summary
Symbol	EGLN3
Name	egl-9 family hypoxia-inducible factor 3
Aliases	PHD3; HIFPH3; HIF prolyl hydroxylase 3; EGL nine (C.elegans) homolog 3; egl nine homolog 3 (C. elegans); HIF ......
Chromosomal Location	14q12
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Transcriptomic and genomic profiling of pre-treated tumor biopsies from responders and non-responders to immunotherapy. These data were used to identify signatures and mechanisms of response to checkpoint blockade (e.g., anti-PDL1 and anti-PD1). One example is that mutations in the gene PBRM1 benefit clinical survival of patients with clear cell renal cell carcinoma. After comprehensively searching, we collected 5 and 6 of transcriptomic and genomic data sets, respectively. In this tab, users can check whether their selected genes have significant difference of expression or mutation between responders and non-responders in various data sets. > Expression difference between responders and non-responders > Mutation difference between responders and non-responders

> Expression difference between responders and non-responders

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Points in the above scatter plot represent the expression difference of EGLN3 in various data sets.

No	PMID	Cancer type	Group	Drug	# Res	# NRes	Log2 (Fold Change)	P value
1	26997480	Melanoma	all	Anti-PD-1 (pembrolizumab and nivolumab)	14	12	-0.137	0.76
2	26997480	Melanoma	MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	6	5	-1.013	0.396
3	26997480	Melanoma	non-MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	8	7	0.502	0.591
4	28552987	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	9	16	0.027	0.958
5	28552987	Urothelial cancer	smoking	Anti-PD-L1 (atezolizumab)	5	9	0.51	0.77
6	28552987	Urothelial cancer	non-smoking	Anti-PD-L1 (atezolizumab)	4	7	-0.588	0.778
7	29033130	Melanoma	all	Anti-PD-1 (nivolumab)	26	23	-0.163	0.714
8	29033130	Melanoma	NIV3-PROG	Anti-PD-1 (nivolumab)	15	11	0.69	0.541
9	29033130	Melanoma	NIV3-NAIVE	Anti-PD-1 (nivolumab)	11	12	-1.092	0.369
10	29301960	Clear cell renal cell carcinoma (ccRCC)	all	Anti-PD-1 (nivolumab)	4	8	-0.091	0.968
11	29301960	Clear cell renal cell carcinoma (ccRCC)	VEGFRi	Anti-PD-1 (nivolumab)	2	0	0	1
12	29301960	Clear cell renal cell carcinoma (ccRCC)	non-VEGFRi	Anti-PD-1 (nivolumab)	2	8	0.492	0.885
13	29443960	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	68	230	-0.087	0.681

> Mutation difference between responders and non-responders

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Points in the above scatter plot represent the mutation difference of EGLN3 in various data sets.

No	PMID	Cancer type	Group	Drug	# Res	# NRes	% Mut/NRes	% Diff (R vs NR)	Pval
1	25765070	Non-small cell lung cancer (NSCLC)	all	Anti-PD-1 (pembrolizumab)	14	17	0	0	1
2	25765070	Non-small cell lung cancer (NSCLC)	smoking	Anti-PD-1 (pembrolizumab)	10	3	0	0	1
3	25765070	Non-small cell lung cancer (NSCLC)	non-smoking	Anti-PD-1 (pembrolizumab)	4	14	0	0	1
4	26359337	Melanoma	all	Anti-CTLA-4 (ipilimumab)	27	73	4.1	-4.1	0.561
5	26359337	Melanoma	BRAFi	Anti-CTLA-4 (ipilimumab)	0	14	0	0	1
6	26359337	Melanoma	non-BRAFi	Anti-CTLA-4 (ipilimumab)	27	59	5.1	-5.1	0.549
7	26997480	Melanoma	all	Anti-PD-1 (pembrolizumab and nivolumab)	21	17	0	0	1
8	26997480	Melanoma	MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	8	6	0	0	1
9	26997480	Melanoma	non-MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	13	11	0	0	1
10	28552987	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	9	16	0	0	1
11	28552987	Urothelial cancer	smoking	Anti-PD-L1 (atezolizumab)	5	9	0	0	1
12	28552987	Urothelial cancer	non-smoking	Anti-PD-L1 (atezolizumab)	4	7	0	0	1
13	29033130	Melanoma	all	Anti-PD-1 (nivolumab)	38	27	0	0	1
14	29033130	Melanoma	NIV3-PROG	Anti-PD-1 (nivolumab)	22	13	0	0	1
15	29033130	Melanoma	NIV3-NAIVE	Anti-PD-1 (nivolumab)	16	14	0	0	1
16	29301960	Clear cell renal cell carcinoma (ccRCC)	all	Anti-PD-1 (nivolumab)	11	13	0	0	1
17	29301960	Clear cell renal cell carcinoma (ccRCC)	VEGFRi	Anti-PD-1 (nivolumab)	6	1	0	0	1
18	29301960	Clear cell renal cell carcinoma (ccRCC)	non-VEGFRi	Anti-PD-1 (nivolumab)	5	12	0	0	1

Summary
Symbol	EGLN3
Name	egl-9 family hypoxia-inducible factor 3
Aliases	PHD3; HIFPH3; HIF prolyl hydroxylase 3; EGL nine (C.elegans) homolog 3; egl nine homolog 3 (C. elegans); HIF ......
Chromosomal Location	14q12
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between abundance of tumor-infiltrating lymphocytes (TILs) and expression, copy number, methylation, or mutation of EGLN3. The immune-related signatures of 28 TIL types from Charoentong's study, which can be viewed in the download page. For each cancer type, the relative abundance of TILs were inferred by using gene set variation analysis (GSVA) based on gene expression profile. In this tab, users can examine which kinds of TILs might be regulated by the current gene.

> Lymphocyte [ TOP ]

Summary
Symbol	EGLN3
Name	egl-9 family hypoxia-inducible factor 3
Aliases	PHD3; HIFPH3; HIF prolyl hydroxylase 3; EGL nine (C.elegans) homolog 3; egl nine homolog 3 (C. elegans); HIF ......
Chromosomal Location	14q12
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between three kinds of immunomodulators and expression, copy number, methylation, or mutation of EGLN3. These immunomo-dulators were collected from Charoentong's study. In this tab, users can examine which immunomodulators might be regulated by EGLN3. > Immunoinhibitor > Immunostimulator > MHC molecule

> Immunoinhibitor [ TOP ]

> Immunostimulator [ TOP ]

> MHC molecule [ TOP ]

Summary
Symbol	EGLN3
Name	egl-9 family hypoxia-inducible factor 3
Aliases	PHD3; HIFPH3; HIF prolyl hydroxylase 3; EGL nine (C.elegans) homolog 3; egl nine homolog 3 (C. elegans); HIF ......
Chromosomal Location	14q12
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between chemokines (or receptors) and expression, copy number, methylation, or mutation of EGLN3. In this tab, users can examine which chemokines (or receptors) might be regulated by the current gene. > Chemokine > Receptor

> Chemokine [ TOP ]

> Receptor [ TOP ]

Summary
Symbol	EGLN3
Name	egl-9 family hypoxia-inducible factor 3
Aliases	PHD3; HIFPH3; HIF prolyl hydroxylase 3; EGL nine (C.elegans) homolog 3; egl nine homolog 3 (C. elegans); HIF ......
Chromosomal Location	14q12
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Distribution of EGLN3 expression across immune and molecular subtypes. > Immune subtype > Molecular subtype

> Immune subtype [ TOP ]

> Molecular subtype [ TOP ]

Summary
Symbol	EGLN3
Name	egl-9 family hypoxia-inducible factor 3
Aliases	PHD3; HIFPH3; HIF prolyl hydroxylase 3; EGL nine (C.elegans) homolog 3; egl nine homolog 3 (C. elegans); HIF ......
Chromosomal Location	14q12
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Associations between EGLN3 and clinical features. > Overall survival analysis > Cancer stage > Tumor grade

> Overall survival [ TOP ]

> Stage [ TOP ]

> Grade [ TOP ]

Summary
Symbol	EGLN3
Name	egl-9 family hypoxia-inducible factor 3
Aliases	PHD3; HIFPH3; HIF prolyl hydroxylase 3; EGL nine (C.elegans) homolog 3; egl nine homolog 3 (C. elegans); HIF ......
Chromosomal Location	14q12
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Drugs targeting EGLN3 collected from DrugBank database.

> Drugs from DrugBank database

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Details on drugs targeting EGLN3.

ID	Name	Drug Type	Targets	#Targets
DB00126	Vitamin C	Small Molecule	ALKBH2, ALKBH3, BBOX1, DBH, EGLN1, EGLN2, EGLN3, KDM5D, LCT, OGFOD ......	23
DB04847	Roxadustat	Small Molecule	EGLN1, EGLN2, EGLN3	3

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