Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTHLP1J3)

• DOT Name: Eyes absent homolog 3 (EYA3)
• Synonyms: EC 3.1.3.48
• Gene Name: EYA3
• Related Disease:
  Breast neoplasm
  Ewing sarcoma
  High blood pressure
  Pulmonary arterial hypertension
  Triple negative breast cancer
  Neoplasm
• UniProt ID: EYA3_HUMAN
• EC Number: 3.1.3.48
• Pfam ID: PF00702
• Sequence:
  MEEEQDLPEQPVKKAKMQESGEQTISQVSNPDVSDQKPETSSLASNLPMSEEIMTCTDYI
  PRSSNDYTSQMYSAKPYAHILSVPVSETAYPGQTQYQTLQQTQPYAVYPQATQTYGLPPF
  GALWPGMKPESGLIQTPSPSQHSVLTCTTGLTTSQPSPAHYSYPIQASSTNASLISTSST
  IANIPAAAVASISNQDYPTYTILGQNQYQACYPSSSFGVTGQTNSDAESTTLAATTYQSE
  KPSVMAPAPAAQRLSSGDPSTSPSLSQTTPSKDTDDQSRKNMTSKNRGKRKADATSSQDS
  ELERVFLWDLDETIIIFHSLLTGSYAQKYGKDPTVVIGSGLTMEEMIFEVADTHLFFNDL
  EECDQVHVEDVASDDNGQDLSNYSFSTDGFSGSGGSGSHGSSVGVQGGVDWMRKLAFRYR
  KVREIYDKHKSNVGGLLSPQRKEALQRLRAEIEVLTDSWLGTALKSLLLIQSRKNCVNVL
  ITTTQLVPALAKVLLYGLGEIFPIENIYSATKIGKESCFERIVSRFGKKVTYVVIGDGRD
  EEIAAKQHNMPFWRITNHGDLVSLHQALELDFL
• 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. 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. May be involved in development of the eye.
• 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

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast neoplasm	DISNGJLM	Strong	Biomarker	[1]
Ewing sarcoma	DISQYLV3	Strong	Biomarker	[2]
High blood pressure	DISY2OHH	Strong	Altered Expression	[3]
Pulmonary arterial hypertension	DISP8ZX5	Strong	Biomarker	[3]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[1]
Neoplasm	DISZKGEW	Disputed	Biomarker	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Eyes absent homolog 3 (EYA3).	[5]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Eyes absent homolog 3 (EYA3).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Eyes absent homolog 3 (EYA3).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Eyes absent homolog 3 (EYA3).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Eyes absent homolog 3 (EYA3).	[9]
Benzbromarone	DMC3YUA	Approved	Benzbromarone decreases the activity of Eyes absent homolog 3 (EYA3).	[11]
PMID28870136-Compound-48	DMPIM9L	Patented	PMID28870136-Compound-48 increases the expression of Eyes absent homolog 3 (EYA3).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Eyes absent homolog 3 (EYA3).	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Eyes absent homolog 3 (EYA3).	[5]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Eyes absent homolog 3 (EYA3).	[14]

1 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 3 (EYA3).	[10]

References

• [1] Eya3 promotes breast tumor-associated immune suppression via threonine phosphatase-mediated PD-L1 upregulation.J Clin Invest. 2018 Jun 1;128(6):2535-2550. doi: 10.1172/JCI96784. Epub 2018 May 14.
• [2] EWS/FLI1 regulates EYA3 in Ewing sarcoma via modulation of miRNA-708, resulting in increased cell survival and chemoresistance.Mol Cancer Res. 2012 Aug;10(8):1098-108. doi: 10.1158/1541-7786.MCR-12-0086. Epub 2012 Jun 20.
• [3] The EYA3 tyrosine phosphatase activity promotes pulmonary vascular remodeling in pulmonary arterial hypertension.Nat Commun. 2019 Sep 12;10(1):4143. doi: 10.1038/s41467-019-12226-1.
• [4] An Immunosuppressive Role for Eya3 in TNBC.Cancer Discov. 2018 Aug;8(8):OF8. doi: 10.1158/2159-8290.CD-NB2018-072. Epub 2018 Jun 8.
• [5] 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.
• [6] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [7] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [8] 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.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] 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.
• [11] The EYA tyrosine phosphatase activity is pro-angiogenic and is inhibited by benzbromarone. PLoS One. 2012;7(4):e34806. doi: 10.1371/journal.pone.0034806. Epub 2012 Apr 24.
• [12] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [13] Characterization of the Molecular Alterations Induced by the Prolonged Exposure of Normal Colon Mucosa and Colon Cancer Cells to Low-Dose Bisphenol A. Int J Mol Sci. 2022 Oct 1;23(19):11620. doi: 10.3390/ijms231911620.
• [14] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.