TISIDB

Summary
Symbol	EYA3
Name	EYA transcriptional coactivator and phosphatase 3
Aliases	DKFZp686C132; eyes absent (Drosophila) homolog 3; eyes absent homolog 3 (Drosophila); eyes absent 3; Eyes ab ......
Chromosomal Location	1p36
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	Cytoplasm Nucleus Note=Localizes at sites of DNA damage at double-strand breaks (DSBs) (PubMed:19234442). With decreasing efficiency, translocalized to the nucleus by SIX2 and SIX5, and SIX4, respectively (By similarity).
Domain	-
Function	Tyrosine phosphatase that specifically dephosphorylates 'Tyr-142' of histone H2AX (H2AXY142ph). 'Tyr-142' phosphorylation of histone H2AX plays a central role in DNA repair and acts as a mark that distinguishes between apoptotic and repair responses to genotoxic stress. Promotes efficient DNA repair by dephosphorylating H2AX, promoting the recruitment of DNA repair complexes containing MDC1 (PubMed:19234442, PubMed:19351884). Its function as histone phosphatase probably explains its role in transcription regulation during organogenesis. Coactivates SIX1, and seems to coactivate SIX2, SIX4 and SIX5. The repression of precursor cell proliferation in myoblasts by SIX1 is switched to activation through recruitment of EYA3 to the SIX1-DACH1 complex and seems to be dependent on EYA3 phosphatase activity (By similarity). May be involved in development of the eye.

> Gene Ontology [ TOP ]
Biological Process	GO:0006282 regulation of DNA repair GO:0006302 double-strand break repair GO:0006470 protein dephosphorylation GO:0007601 visual perception GO:0009314 response to radiation GO:0010212 response to ionizing radiation GO:0016311 dephosphorylation GO:0016570 histone modification GO:0016576 histone dephosphorylation GO:0035335 peptidyl-tyrosine dephosphorylation GO:0038034 signal transduction in absence of ligand GO:0045739 positive regulation of DNA repair GO:0050953 sensory perception of light stimulus GO:0051052 regulation of DNA metabolic process GO:0051054 positive regulation of DNA metabolic process GO:0097191 extrinsic apoptotic signaling pathway GO:0097192 extrinsic apoptotic signaling pathway in absence of ligand GO:1901099 negative regulation of signal transduction in absence of ligand GO:2001020 regulation of response to DNA damage stimulus GO:2001022 positive regulation of response to DNA damage stimulus GO:2001233 regulation of apoptotic signaling pathway GO:2001234 negative regulation of apoptotic signaling pathway GO:2001236 regulation of extrinsic apoptotic signaling pathway GO:2001237 negative regulation of extrinsic apoptotic signaling pathway GO:2001239 regulation of extrinsic apoptotic signaling pathway in absence of ligand GO:2001240 negative regulation of extrinsic apoptotic signaling pathway in absence of ligand
Molecular Function	GO:0004721 phosphoprotein phosphatase activity GO:0004725 protein tyrosine phosphatase activity GO:0016791 phosphatase activity GO:0042578 phosphoric ester hydrolase activity
Cellular Component	GO:0005667 transcription factor complex GO:0005813 centrosome

> KEGG and Reactome Pathway [ TOP ]
KEGG	-
Reactome	R-HSA-5693606: DNA Double Strand Break Response R-HSA-5693532: DNA Double-Strand Break Repair R-HSA-73894: DNA Repair R-HSA-5693565: Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks

Summary
Symbol	EYA3
Name	EYA transcriptional coactivator and phosphatase 3
Aliases	DKFZp686C132; eyes absent (Drosophila) homolog 3; eyes absent homolog 3 (Drosophila); eyes absent 3; Eyes ab ......
Chromosomal Location	1p36
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Literatures that report relations between EYA3 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 EYA3 and anti-tumor immunity in human cancer.

PMID	Cancer type	Relation to immunity	Evidence sentences
29884726	Triple-Negative Breast Carcinoma	Inhibit immunity	A recent study indicates that the protein Eya3 influences the adaptive immune response to promote tumor growth, not only decreasing the number of tumor-infiltrating CD8+ T cells, but also driving their exhaustion through PD-L1 upregulation.
29757193	Triple-Negative Breast Carcinoma	Inhibit immunity (infiltration)	Eya3 promotes breast tumor-associated immune suppression via threonine phosphatase-mediated PD-L1 upregulation. Eya3 loss decreases tumor growth in immune-competent mice and is associated with increased numbers of infiltrated CD8+ T cells, which, when depleted, reverse the effects of Eya3 knockdown. Mechanistically, Eya3 utilizes its Thr phosphatase activity to dephosphorylate Myc at pT58, resulting in a stabilized form. We show that Myc is required for Eya3-mediated increases in PD-L1, and that rescue of PD-L1 in Eya3-knockdown cells restores tumor progression. Finally, we demonstrate that Eya3 significantly correlates with PD-L1 in human breast tumors, and that tumors expressing high levels of Eya3 have a decreased CD8+ T cell signature.

Summary
Symbol	EYA3
Name	EYA transcriptional coactivator and phosphatase 3
Aliases	DKFZp686C132; eyes absent (Drosophila) homolog 3; eyes absent homolog 3 (Drosophila); eyes absent 3; Eyes ab ......
Chromosomal Location	1p36
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 EYA3 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	EYA3
Name	EYA transcriptional coactivator and phosphatase 3
Aliases	DKFZp686C132; eyes absent (Drosophila) homolog 3; eyes absent homolog 3 (Drosophila); eyes absent 3; Eyes ab ......
Chromosomal Location	1p36
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 EYA3 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	0.039	0.829
2	26997480	Melanoma	MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	6	5	0.332	0.81
3	26997480	Melanoma	non-MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	8	7	-0.172	0.86
4	28552987	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	9	16	-0.068	0.83
5	28552987	Urothelial cancer	smoking	Anti-PD-L1 (atezolizumab)	5	9	0.223	0.907
6	28552987	Urothelial cancer	non-smoking	Anti-PD-L1 (atezolizumab)	4	7	-0.437	0.854
7	29033130	Melanoma	all	Anti-PD-1 (nivolumab)	26	23	0.117	0.725
8	29033130	Melanoma	NIV3-PROG	Anti-PD-1 (nivolumab)	15	11	0.061	0.968
9	29033130	Melanoma	NIV3-NAIVE	Anti-PD-1 (nivolumab)	11	12	0.179	0.916
10	29301960	Clear cell renal cell carcinoma (ccRCC)	all	Anti-PD-1 (nivolumab)	4	8	0.192	0.855
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	0.609	0.677
13	29443960	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	68	230	0.072	0.165

> Mutation difference between responders and non-responders

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Points in the above scatter plot represent the mutation difference of EYA3 in various data sets.

No	PMID	Cancer type	Group	Drug	# Res	# NRes	% Mut/Res	% Mut/NRes	% Diff (R vs NR)	Pval
1	25765070	Non-small cell lung cancer (NSCLC)	all	Anti-PD-1 (pembrolizumab)	14	17	0	0	0	1
2	25765070	Non-small cell lung cancer (NSCLC)	smoking	Anti-PD-1 (pembrolizumab)	10	3	0	0	0	1
3	25765070	Non-small cell lung cancer (NSCLC)	non-smoking	Anti-PD-1 (pembrolizumab)	4	14	0	0	0	1
4	26359337	Melanoma	all	Anti-CTLA-4 (ipilimumab)	27	73	3.7	2.7	1	1
5	26359337	Melanoma	BRAFi	Anti-CTLA-4 (ipilimumab)	0	14	0	7.1	-7.1	1
6	26359337	Melanoma	non-BRAFi	Anti-CTLA-4 (ipilimumab)	27	59	3.7	1.7	2	0.532
7	26997480	Melanoma	all	Anti-PD-1 (pembrolizumab and nivolumab)	21	17	4.8	0	4.8	1
8	26997480	Melanoma	MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	8	6	12.5	0	12.5	1
9	26997480	Melanoma	non-MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	13	11	0	0	0	1
10	28552987	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	9	16	0	0	0	1
11	28552987	Urothelial cancer	smoking	Anti-PD-L1 (atezolizumab)	5	9	0	0	0	1
12	28552987	Urothelial cancer	non-smoking	Anti-PD-L1 (atezolizumab)	4	7	0	0	0	1
13	29033130	Melanoma	all	Anti-PD-1 (nivolumab)	38	27	0	0	0	1
14	29033130	Melanoma	NIV3-PROG	Anti-PD-1 (nivolumab)	22	13	0	0	0	1
15	29033130	Melanoma	NIV3-NAIVE	Anti-PD-1 (nivolumab)	16	14	0	0	0	1
16	29301960	Clear cell renal cell carcinoma (ccRCC)	all	Anti-PD-1 (nivolumab)	11	13	0	0	0	1
17	29301960	Clear cell renal cell carcinoma (ccRCC)	VEGFRi	Anti-PD-1 (nivolumab)	6	1	0	0	0	1
18	29301960	Clear cell renal cell carcinoma (ccRCC)	non-VEGFRi	Anti-PD-1 (nivolumab)	5	12	0	0	0	1

Summary
Symbol	EYA3
Name	EYA transcriptional coactivator and phosphatase 3
Aliases	DKFZp686C132; eyes absent (Drosophila) homolog 3; eyes absent homolog 3 (Drosophila); eyes absent 3; Eyes ab ......
Chromosomal Location	1p36
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between abundance of tumor-infiltrating lymphocytes (TILs) and expression, copy number, methylation, or mutation of EYA3. 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	EYA3
Name	EYA transcriptional coactivator and phosphatase 3
Aliases	DKFZp686C132; eyes absent (Drosophila) homolog 3; eyes absent homolog 3 (Drosophila); eyes absent 3; Eyes ab ......
Chromosomal Location	1p36
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between three kinds of immunomodulators and expression, copy number, methylation, or mutation of EYA3. These immunomo-dulators were collected from Charoentong's study. In this tab, users can examine which immunomodulators might be regulated by EYA3. > Immunoinhibitor > Immunostimulator > MHC molecule

> Immunoinhibitor [ TOP ]

> Immunostimulator [ TOP ]

> MHC molecule [ TOP ]

Summary
Symbol	EYA3
Name	EYA transcriptional coactivator and phosphatase 3
Aliases	DKFZp686C132; eyes absent (Drosophila) homolog 3; eyes absent homolog 3 (Drosophila); eyes absent 3; Eyes ab ......
Chromosomal Location	1p36
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between chemokines (or receptors) and expression, copy number, methylation, or mutation of EYA3. 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	EYA3
Name	EYA transcriptional coactivator and phosphatase 3
Aliases	DKFZp686C132; eyes absent (Drosophila) homolog 3; eyes absent homolog 3 (Drosophila); eyes absent 3; Eyes ab ......
Chromosomal Location	1p36
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Distribution of EYA3 expression across immune and molecular subtypes. > Immune subtype > Molecular subtype

> Immune subtype [ TOP ]

> Molecular subtype [ TOP ]

Summary
Symbol	EYA3
Name	EYA transcriptional coactivator and phosphatase 3
Aliases	DKFZp686C132; eyes absent (Drosophila) homolog 3; eyes absent homolog 3 (Drosophila); eyes absent 3; Eyes ab ......
Chromosomal Location	1p36
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Associations between EYA3 and clinical features. > Overall survival analysis > Cancer stage > Tumor grade

> Overall survival [ TOP ]

> Stage [ TOP ]

> Grade [ TOP ]

Summary
Symbol	EYA3
Name	EYA transcriptional coactivator and phosphatase 3
Aliases	DKFZp686C132; eyes absent (Drosophila) homolog 3; eyes absent homolog 3 (Drosophila); eyes absent 3; Eyes ab ......
Chromosomal Location	1p36
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Drugs targeting EYA3 collected from DrugBank database.

> Drugs from DrugBank database [ TOP ]
There is no record.

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