Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTINGR3Z)

• DOT Name: Eyes absent homolog 4 (EYA4)
• Synonyms: EC 3.1.3.48
• Gene Name: EYA4
• Related Disease:
  Advanced cancer
  Holoprosencephaly
  Nonsyndromic genetic hearing loss
  Waardenburg syndrome type 1
  Alzheimer disease
  Autosomal dominant nonsyndromic hearing loss 10
  Branchio-oto-renal syndrome
  Carcinoma of esophagus
  Cardiac failure
  Cardiomyopathy
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Deafness
  Dilated cardiomyopathy
  Dilated cardiomyopathy 1A
  Esophageal cancer
  Esophageal squamous cell carcinoma
  Glioma
  Hepatocellular carcinoma
  Intrahepatic cholangiocarcinoma
  Lung adenocarcinoma
  Lung neoplasm
  Malignant peripheral nerve sheath tumor
  Movement disorder
  Neoplasm
  Neoplasm of esophagus
  Non-small-cell lung cancer
  Oculodentodigital dysplasia
  Oral cancer
  Otitis media
  Otofaciocervical syndrome
  Otofaciocervical syndrome 1
  Precancerous condition
  Sensorineural hearing loss disorder
  Adenocarcinoma
  Barrett esophagus
  Bladder cancer
  Congestive heart failure
  Urinary bladder cancer
  Urinary bladder neoplasm
  Autosomal dominant nonsyndromic hearing loss
  Dilated cardiomyopathy 1J
  Colorectal neoplasm
  Intellectual disability
  Matthew-Wood syndrome
  Pancreatic ductal carcinoma
• UniProt ID: EYA4_HUMAN
• EC Number: 3.1.3.48
• Pfam ID: PF00702
• Sequence:
  MEDSQDLNEQSVKKTCTESDVSQSQNSRSMEMQDLASPHTLVGGGDTPGSSKLEKSNLSS
  TSVTTNGTGGENMTVLNTADWLLSCNTPSSATMSLLAVKTEPLNSSETTATTGDGALDTF
  TGSVITSSGYSPRSAHQYSPQLYPSKPYPHILSTPAAQTMSAYAGQTQYSGMQQPAVYTA
  YSQTGQPYSLPTYDLGVMLPAIKTESGLSQTQSPLQSGCLSYSPGFSTPQPGQTPYSYQM
  PGSSFAPSSTIYANNSVSNSTNFSGSQQDYPSYTAFGQNQYAQYYSASTYGAYMTSNNTA
  DGTPSSTSTYQLQESLPGLTNQPGEFDTMQSPSTPIKDLDERTCRSSGSKSRGRGRKNNP
  SPPPDSDLERVFVWDLDETIIVFHSLLTGSYAQKYGKDPPMAVTLGLRMEEMIFNLADTH
  LFFNDLEECDQVHIDDVSSDDNGQDLSTYSFATDGFHAAASSANLCLPTGVRGGVDWMRK
  LAFRYRRVKELYNTYKNNVGGLLGPAKRDAWLQLRAEIEGLTDSWLTNALKSLSIISTRS
  NCINVLVTTTQLIPALAKVLLYSLGGAFPIENIYSATKIGKESCFERIMQRFGRKVVYVV
  IGDGVEEEQAAKKHNMPFWRISSHSDLLALHQALELEYL
• 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. Its function as histone phosphatase probably explains its role in transcription regulation during organogenesis. May be involved in development of the eye.
• Tissue Specificity: Highly expressed in heart and skeletal muscle.
• Reactome Pathway: Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks (R-HSA-5693565)

Molecular Interaction Atlas (MIA) of This DOT

47 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Definitive	Biomarker	[1]
Holoprosencephaly	DISR35EC	Definitive	Biomarker	[2]
Nonsyndromic genetic hearing loss	DISZX61P	Definitive	Autosomal dominant	[3]
Waardenburg syndrome type 1	DIS8DBQ5	Definitive	Genetic Variation	[4]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[5]
Autosomal dominant nonsyndromic hearing loss 10	DISBEWBO	Strong	Autosomal dominant	[6]
Branchio-oto-renal syndrome	DISIPQ53	Strong	Biomarker	[7]
Carcinoma of esophagus	DISS6G4D	Strong	Biomarker	[8]
Cardiac failure	DISDC067	Strong	Altered Expression	[9]
Cardiomyopathy	DISUPZRG	Strong	Genetic Variation	[10]
Colon cancer	DISVC52G	Strong	Biomarker	[11]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[11]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[12]
Deafness	DISKCLH4	Strong	Genetic Variation	[13]
Dilated cardiomyopathy	DISX608J	Strong	Biomarker	[14]
Dilated cardiomyopathy 1A	DIS0RK9Z	Strong	Genetic Variation	[14]
Esophageal cancer	DISGB2VN	Strong	Biomarker	[8]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[15]
Glioma	DIS5RPEH	Strong	Altered Expression	[1]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[16]
Intrahepatic cholangiocarcinoma	DIS6GOC8	Strong	Altered Expression	[17]
Lung adenocarcinoma	DISD51WR	Strong	Posttranslational Modification	[18]
Lung neoplasm	DISVARNB	Strong	Biomarker	[19]
Malignant peripheral nerve sheath tumor	DIS0JTN6	Strong	Biomarker	[20]
Movement disorder	DISOJJ2D	Strong	CausalMutation	[21]
Neoplasm	DISZKGEW	Strong	Biomarker	[16]
Neoplasm of esophagus	DISOLKAQ	Strong	Biomarker	[8]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[19]
Oculodentodigital dysplasia	DISSWR9C	Strong	Altered Expression	[22]
Oral cancer	DISLD42D	Strong	Biomarker	[23]
Otitis media	DISGZDUO	Strong	Biomarker	[24]
Otofaciocervical syndrome	DISLYABR	Strong	Genetic Variation	[25]
Otofaciocervical syndrome 1	DISZJB3G	Strong	Biomarker	[25]
Precancerous condition	DISV06FL	Strong	Altered Expression	[8]
Sensorineural hearing loss disorder	DISJV45Z	Strong	Biomarker	[26]
Adenocarcinoma	DIS3IHTY	moderate	Posttranslational Modification	[27]
Barrett esophagus	DIS416Y7	moderate	Altered Expression	[27]
Bladder cancer	DISUHNM0	moderate	Biomarker	[28]
Congestive heart failure	DIS32MEA	moderate	Altered Expression	[9]
Urinary bladder cancer	DISDV4T7	moderate	Biomarker	[28]
Urinary bladder neoplasm	DIS7HACE	moderate	Biomarker	[28]
Autosomal dominant nonsyndromic hearing loss	DISYC1G0	Supportive	Autosomal dominant	[29]
Dilated cardiomyopathy 1J	DIS953V6	Supportive	Autosomal dominant	[9]
Colorectal neoplasm	DISR1UCN	Disputed	Biomarker	[30]
Intellectual disability	DISMBNXP	Limited	Genetic Variation	[31]
Matthew-Wood syndrome	DISA7HR7	Limited	Altered Expression	[32]
Pancreatic ductal carcinoma	DIS26F9Q	Limited	Biomarker	[32]

12 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Eyes absent homolog 4 (EYA4).	[33]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Eyes absent homolog 4 (EYA4).	[34]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Eyes absent homolog 4 (EYA4).	[35]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Eyes absent homolog 4 (EYA4).	[37]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Eyes absent homolog 4 (EYA4).	[38]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Eyes absent homolog 4 (EYA4).	[39]
Dexamethasone	DMMWZET	Approved	Dexamethasone affects the expression of Eyes absent homolog 4 (EYA4).	[40]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Eyes absent homolog 4 (EYA4).	[38]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Eyes absent homolog 4 (EYA4).	[42]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Eyes absent homolog 4 (EYA4).	[44]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Eyes absent homolog 4 (EYA4).	[45]
Manganese	DMKT129	Investigative	Manganese decreases the expression of Eyes absent homolog 4 (EYA4).	[46]

3 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Eyes absent homolog 4 (EYA4).	[36]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Eyes absent homolog 4 (EYA4).	[41]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Eyes absent homolog 4 (EYA4).	[43]

References

• [1] EYA4 Promotes Cell Proliferation Through Downregulation of p27Kip1 in Glioma.Cell Physiol Biochem. 2018;49(5):1856-1869. doi: 10.1159/000493631. Epub 2018 Sep 19.
• [2] EYA4, deleted in a case with middle interhemispheric variant of holoprosencephaly, interacts with SIX3 both physically and functionally.Hum Mutat. 2009 Oct;30(10):E946-55. doi: 10.1002/humu.21094.
• [3] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [4] A novel mutation of the EYA4 gene associated with post-lingual hearing loss in a proband is co-segregating with a novel PAX3 mutation in two congenitally deaf family members.Int J Pediatr Otorhinolaryngol. 2018 Jan;104:88-93. doi: 10.1016/j.ijporl.2017.10.042. Epub 2017 Oct 31.
• [5] Family-based association analyses of imputed genotypes reveal genome-wide significant association of Alzheimer's disease with OSBPL6, PTPRG, and PDCL3.Mol Psychiatry. 2016 Nov;21(11):1608-1612. doi: 10.1038/mp.2015.218. Epub 2016 Feb 2.
• [6] Mutations in the transcriptional activator EYA4 cause late-onset deafness at the DFNA10 locus. Hum Mol Genet. 2001 Feb 1;10(3):195-200. doi: 10.1093/hmg/10.3.195.
• [7] A comparative study of Eya1 and Eya4 protein function and its implication in branchio-oto-renal syndrome and DFNA10.J Assoc Res Otolaryngol. 2004 Sep;5(3):295-304. doi: 10.1007/s10162-004-4044-3. Epub 2004 Jun 24.
• [8] Relationship between the expression of hTERT and EYA4 mRNA in peripheral blood mononuclear cells with the progressive stages of carcinogenesis of the esophagus.J Exp Clin Cancer Res. 2009 Nov 25;28(1):145. doi: 10.1186/1756-9966-28-145.
• [9] Mutation in the transcriptional coactivator EYA4 causes dilated cardiomyopathy and sensorineural hearing loss. Nat Genet. 2005 Apr;37(4):418-22. doi: 10.1038/ng1527. Epub 2005 Feb 27.
• [10] Eya4 Induces Hypertrophy via Regulation of p27kip1.Circ Cardiovasc Genet. 2015 Dec;8(6):752-64. doi: 10.1161/CIRCGENETICS.115.001134. Epub 2015 Oct 23.
• [11] Novel method for high throughput DNA methylation marker evaluation using PNA-probe library hybridization and MALDI-TOF detection.Nucleic Acids Res. 2006 May 2;34(8):e59. doi: 10.1093/nar/gkl218.
• [12] EYA4 Acts as a New Tumor Suppressor Gene in Colorectal Cancer.Mol Carcinog. 2015 Dec;54(12):1748-57. doi: 10.1002/mc.22247. Epub 2015 Jan 25.
• [13] Identification of a novel missense eya4 mutation causing autosomal dominant nonsyndromic hearing loss in a chinese family.Cell Mol Biol (Noisy-le-grand). 2019 Mar 31;65(3):84-88.
• [14] Nonsyndromic hearing loss DFNA10 and a novel mutation of EYA4: evidence for correlation of normal cardiac phenotype with truncating mutations of the Eya domain.Am J Med Genet A. 2007 Jul 15;143A(14):1592-8. doi: 10.1002/ajmg.a.31793.
• [15] Aberrant methylation of EYA4 promotes epithelial-mesenchymal transition in esophageal squamous cell carcinoma.Cancer Sci. 2018 Jun;109(6):1811-1824. doi: 10.1111/cas.13615. Epub 2018 May 26.
• [16] EYA4 serves as a prognostic biomarker in hepatocellular carcinoma and suppresses tumour angiogenesis and metastasis.J Cell Mol Med. 2019 Jun;23(6):4208-4216. doi: 10.1111/jcmm.14309. Epub 2019 Apr 7.
• [17] EYA4 gene functions as a prognostic marker and inhibits the growth of intrahepatic cholangiocarcinoma.Chin J Cancer. 2016 Jul 28;35(1):70. doi: 10.1186/s40880-016-0133-z.
• [18] DNA methylation profiling identifies the HOXA11 gene as an early diagnostic and prognostic molecular marker in human lung adenocarcinoma.Oncotarget. 2017 May 16;8(20):33100-33109. doi: 10.18632/oncotarget.16528.
• [19] EYA4 is inactivated biallelically at a high frequency in sporadic lung cancer and is associated with familial lung cancer risk.Oncogene. 2014 Sep 4;33(36):4464-73. doi: 10.1038/onc.2013.396. Epub 2013 Oct 7.
• [20] Inhibition of Eyes Absent Homolog 4 expression induces malignant peripheral nerve sheath tumor necrosis.Oncogene. 2010 Jan 21;29(3):368-79. doi: 10.1038/onc.2009.360. Epub 2009 Nov 9.
• [21] Research progress in pathogenic genes of hereditary non-syndromic mid-frequency deafness.Front Med. 2016 Jun;10(2):137-42. doi: 10.1007/s11684-016-0449-8. Epub 2016 May 3.
• [22] EYA4, a novel vertebrate gene related to Drosophila eyes absent.Hum Mol Genet. 1999 Jan;8(1):11-23. doi: 10.1093/hmg/8.1.11.
• [23] Epigenetic mediated silencing of EYA4 contributes to tumorigenesis in oral dysplastic cells.Genes Chromosomes Cancer. 2016 Jul;55(7):568-76. doi: 10.1002/gcc.22360. Epub 2016 May 2.
• [24] Eya4-deficient mice are a model for heritable otitis media.J Clin Invest. 2008 Feb;118(2):651-8. doi: 10.1172/JCI32899.
• [25] Familial Interstitial 6q23.2 Deletion Including Eya4 Associated With Otofaciocervical Syndrome.Front Genet. 2019 Jul 18;10:650. doi: 10.3389/fgene.2019.00650. eCollection 2019.
• [26] Expression pattern of EYA4 in the common marmoset (Callithrix jacchus) cochlea.Neurosci Lett. 2018 Jan 1;662:185-188. doi: 10.1016/j.neulet.2017.10.030. Epub 2017 Oct 18.
• [27] Frequent methylation of eyes absent 4 gene in Barrett's esophagus and esophageal adenocarcinoma.Cancer Epidemiol Biomarkers Prev. 2005 Apr;14(4):830-4. doi: 10.1158/1055-9965.EPI-04-0506.
• [28] Circular RNA ACVR2A suppresses bladder cancer cells proliferation and metastasis through miR-626/EYA4 axis.Mol Cancer. 2019 May 17;18(1):95. doi: 10.1186/s12943-019-1025-z.
• [29] Genetic Hearing Loss Overview. 1999 Feb 14 [updated 2023 Sep 28]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [30] Genomic and epigenomic integration identifies a prognostic signature in colon cancer.Clin Cancer Res. 2011 Mar 15;17(6):1535-45. doi: 10.1158/1078-0432.CCR-10-2509. Epub 2011 Jan 28.
• [31] De novo 9 Mb deletion of 6q23.2q24.1 disrupting the gene EYA4 in a patient with sensorineural hearing loss, cardiac malformation, and mental retardation.Eur J Med Genet. 2009 Nov-Dec;52(6):450-3. doi: 10.1016/j.ejmg.2009.06.004. Epub 2009 Jul 1.
• [32] EYA4 functions as tumor suppressor gene and prognostic marker in pancreatic ductal adenocarcinoma through -catenin/ID2 pathway.Cancer Lett. 2016 Oct 1;380(2):403-412. doi: 10.1016/j.canlet.2016.06.021. Epub 2016 Jul 1.
• [33] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [34] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [35] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [36] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [37] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [38] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [39] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [40] Neuronal and cardiac toxicity of pharmacological compounds identified through transcriptomic analysis of human pluripotent stem cell-derived embryoid bodies. Toxicol Appl Pharmacol. 2021 Dec 15;433:115792. doi: 10.1016/j.taap.2021.115792. Epub 2021 Nov 3.
• [41] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [42] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [43] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [44] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [45] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [46] Gene expression profiling of human primary astrocytes exposed to manganese chloride indicates selective effects on several functions of the cells. Neurotoxicology. 2007 May;28(3):478-89.