Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7Z6LX2)

• DOT Name: Espin (ESPN)
• Synonyms: Autosomal recessive deafness type 36 protein; Ectoplasmic specialization protein
• Gene Name: ESPN
• Related Disease:
  Melanoma
  Nonsyndromic genetic hearing loss
  Autosomal recessive nonsyndromic hearing loss 36
  Bartter syndrome
  Esophageal squamous cell carcinoma
  Idiopathic nephrotic syndrome
  Usher syndrome
  Usher syndrome type 2D
  Hearing loss, autosomal recessive
  Usher syndrome type 1
  Chronic renal failure
  Deafness
  End-stage renal disease
  Melanocytic nevus
  Usher syndrome type 3B
  Usher syndrome, type 1M
• UniProt ID: ESPN_HUMAN
• Pfam ID: PF12796 ; PF02205
• Sequence:
  MALEQALQAARQGELDVLRSLHAAGLLGPSLRDPLDALPVHHAARAGKLHCLRFLVEEAA
  LPAAARARNGATPAHDASATGHLACLQWLLSQGGCRVQDKDNSGATVLHLAARFGHPEVV
  NWLLHHGGGDPTAATDMGALPIHYAAAKGDFPSLRLLVEHYPEGVNAQTKNGATPLYLAC
  QEGHLEVTQYLVQECGADPHARAHDGMTPLHAAAQMGHSPVIVWLVSCTDVSLSEQDKDG
  ATAMHFAASRGHTKVLSWLLLHGGEISADLWGGTPLHDAAENGELECCQILVVNGAELDV
  RDRDGYTAADLSDFNGHSHCTRYLRTVENLSVEHRVLSRDPSAELEAKQPDSGMSSPNTT
  VSVQPLNFDLSSPTSTLSNYDSCSSSHSSIKGQHPPCGLSSARAADIQSYMDMLNPELGL
  PRGTIGKPTPPPPPPSFPPPPPPPGTQLPPPPPGYPAPKPPVGPQAADIYMQTKNKLRHV
  ETEALKKELSSCDGHDGLRRQDSSRKPRAFSKQPSTGDYYRQLGRCPGETLAARPGMAHS
  EEVRARQPARAGCPRLGPAARGSLEGPSAPPQAALLPGNHVPNGCAADPKASRELPPPPP
  PPPPPLPEAASSPPPAPPLPLESAGPGCGQRRSSSSTGSTKSFNMMSPTGDNSELLAEIK
  AGKSLKPTPQSKGLTTVFSGIGQPAFQPDSPLPSVSPALSPVRSPTPPAAGFQPLLNGSL
  VPVPPTTPAPGVQLDVEALIPTHDEQGRPIPEWKRQVMVRKMQLKMQEEEEQRRKEEEEE
  ARLASMPAWRRDLLRKKLEEEREQKRKEEERQKQEELRREKEQSEKLRTLGYDESKLAPW
  QRQVILKKGDIAKY
• Function: Multifunctional actin-bundling protein. Plays a major role in regulating the organization, dimension, dynamics and signaling capacities of the actin filament-rich microvilli in the mechanosensory and chemosensory cells. Required for the assembly and stabilization of the stereociliary parallel actin bundles. Plays a crucial role in the formation and maintenance of inner ear hair cell stereocilia. Involved in the elongation of actin in stereocilia. In extrastriolar hair cells, required for targeting MYO3B to stereocilia tips, and for regulation of stereocilia diameter and staircase formation.
• Reactome Pathway:
  Sensory processing of sound by outer hair cells of the cochlea (R-HSA-9662361)
  Sensory processing of sound by inner hair cells of the cochlea (R-HSA-9662360)

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Melanoma	DIS1RRCY	Definitive	Altered Expression	[1]
Nonsyndromic genetic hearing loss	DISZX61P	Definitive	Autosomal recessive	[2]
Autosomal recessive nonsyndromic hearing loss 36	DISCGR8W	Strong	Autosomal recessive	[3]
Bartter syndrome	DIS7D44B	Strong	Biomarker	[4]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[5]
Idiopathic nephrotic syndrome	DISV4XYG	Strong	Biomarker	[6]
Usher syndrome	DIS9YIS7	Strong	Biomarker	[7]
Usher syndrome type 2D	DISHEVUD	Strong	Biomarker	[8]
Hearing loss, autosomal recessive	DIS8G9R9	Supportive	Autosomal recessive	[9]
Usher syndrome type 1	DISR29E4	Supportive	Autosomal recessive	[10]
Chronic renal failure	DISGG7K6	Limited	Biomarker	[11]
Deafness	DISKCLH4	Limited	Genetic Variation	[12]
End-stage renal disease	DISXA7GG	Limited	Biomarker	[11]
Melanocytic nevus	DISYS32D	Limited	Biomarker	[13]
Usher syndrome type 3B	DISPLHUS	Limited	Autosomal recessive	[10]
Usher syndrome, type 1M	DISR8AWK	Limited	Unknown	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Espin (ESPN).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Espin (ESPN).	[25]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Espin (ESPN).	[26]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Espin (ESPN).	[15]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Espin (ESPN).	[16]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Espin (ESPN).	[17]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Espin (ESPN).	[15]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Espin (ESPN).	[18]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Espin (ESPN).	[19]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Espin (ESPN).	[20]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Espin (ESPN).	[21]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Espin (ESPN).	[22]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Espin (ESPN).	[23]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Espin (ESPN).	[24]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Espin (ESPN).	[22]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Espin (ESPN).	[22]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Espin (ESPN).	[22]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Espin (ESPN).	[27]

References

• [1] Overexpression of microRNA-612 Restrains the Growth, Invasion, and Tumorigenesis of Melanoma Cells by Targeting Espin.Mol Cells. 2018 Feb 28;41(2):119-126. doi: 10.14348/molcells.2018.2235. Epub 2018 Jan 29.
• [2] 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.
• [3] Mutations of ESPN cause autosomal recessive deafness and vestibular dysfunction. J Med Genet. 2004 Aug;41(8):591-5. doi: 10.1136/jmg.2004.018523.
• [4] A new autosomal recessive nonsyndromic hearing impairment locus DFNB96 on chromosome 1p36.31-p36.13.J Hum Genet. 2011 Dec;56(12):866-8. doi: 10.1038/jhg.2011.110. Epub 2011 Sep 22.
• [5] An actin-binding protein ESPN is an independent prognosticator and regulates cell growth for esophageal squamous cell carcinoma.Cancer Cell Int. 2018 Dec 29;18:219. doi: 10.1186/s12935-018-0713-x. eCollection 2018.
• [6] European Society of Pediatric Nephrology survey on current practice regarding recurrent focal segmental glomerulosclerosis after pediatric kidney transplantation.Pediatr Transplant. 2019 May;23(3):e13385. doi: 10.1111/petr.13385. Epub 2019 Mar 1.
• [7] Identification of whirlin domains interacting with espin: A study of the mechanism of Usher syndrome typeII.Mol Med Rep. 2019 Dec;20(6):5111-5117. doi: 10.3892/mmr.2019.10728. Epub 2019 Oct 7.
• [8] Whirlin interacts with espin and modulates its actin-regulatory function: an insight into the mechanism of Usher syndrome type II.Hum Mol Genet. 2012 Feb 1;21(3):692-710. doi: 10.1093/hmg/ddr503. Epub 2011 Nov 2.
• [9] 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.
• [10] Inframe deletion of human ESPN is associated with deafness, vestibulopathy and vision impairment. J Med Genet. 2018 Jul;55(7):479-488. doi: 10.1136/jmedgenet-2017-105221. Epub 2018 Mar 23.
• [11] Vascular access in children requiring maintenance haemodialysis: a consensus document by the European Society for Paediatric Nephrology Dialysis Working Group.Nephrol Dial Transplant. 2019 Oct 1;34(10):1746-1765. doi: 10.1093/ndt/gfz011.
• [12] A novel mutation in the Espin gene causes autosomal recessive nonsyndromic hearing loss but no apparent vestibular dysfunction in a Moroccan family.Am J Med Genet A. 2008 Dec 1;146A(23):3086-9. doi: 10.1002/ajmg.a.32525.
• [13] Actin-binding protein, Espin: a novel metastatic regulator for melanoma.Mol Cancer Res. 2014 Mar;12(3):440-6. doi: 10.1158/1541-7786.MCR-13-0468-T. Epub 2013 Dec 13.
• [14] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [15] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [16] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [17] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [18] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [19] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [20] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [21] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [22] Gene expression profiling in Ishikawa cells: a fingerprint for estrogen active compounds. Toxicol Appl Pharmacol. 2009 Apr 1;236(1):85-96.
• [23] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [24] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [25] 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.
• [26] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [27] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.