Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZ6ES6V)

• DOT Name: Epidermal growth factor receptor kinase substrate 8 (EPS8)
• Gene Name: EPS8
• Related Disease:
  Adenoma
  Carcinoma of liver and intrahepatic biliary tract
  Colon cancer
  Colon carcinoma
  Colonic neoplasm
  Colorectal adenoma
  Colorectal carcinoma
  Invasive breast carcinoma
  Liver cancer
  Pancreatic ductal carcinoma
  Acute myelogenous leukaemia
  Adult glioblastoma
  Advanced cancer
  Autism spectrum disorder
  Autosomal recessive nonsyndromic hearing loss 102
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Burkitt lymphoma
  Carcinoma
  Cholangiocarcinoma
  Glioblastoma multiforme
  Glioma
  Malignant glioma
  Matthew-Wood syndrome
  Neoplasm
  Non-small-cell lung cancer
  Squamous cell carcinoma
  Hearing loss, autosomal recessive
  Plasma cell myeloma
  Autism
  Epithelial ovarian cancer
  Head and neck cancer
  Head and neck carcinoma
  Hepatocellular carcinoma
  Intellectual disability
  Lung cancer
  Lung carcinoma
  Metastatic malignant neoplasm
  Ovarian cancer
  Ovarian neoplasm
  Pancreatic cancer
• UniProt ID: EPS8_HUMAN
• PDB ID: 2E8M; 7TZK
• Pfam ID: PF08416 ; PF18016 ; PF00018
• Sequence:
  MNGHISNHPSSFGMYPSQMNGYGSSPTFSQTDREHGSKTSAKALYEQRKNYARDSVSSVS
  DISQYRVEHLTTFVLDRKDAMITVDDGIRKLKLLDAKGKVWTQDMILQVDDRAVSLIDLE
  SKNELENFPLNTIQHCQAVMHSCSYDSVLALVCKEPTQNKPDLHLFQCDEVKANLISEDI
  ESAISDSKGGKQKRRPDALRMISNADPSIPPPPRAPAPAPPGTVTQVDVRSRVAAWSAWA
  ADQGDFEKPRQYHEQEETPEMMAARIDRDVQILNHILDDIEFFITKLQKAAEAFSELSKR
  KKNKKGKRKGPGEGVLTLRAKPPPPDEFLDCFQKFKHGFNLLAKLKSHIQNPSAADLVHF
  LFTPLNMVVQATGGPELASSVLSPLLNKDTIDFLNYTVNGDERQLWMSLGGTWMKARAEW
  PKEQFIPPYVPRFRNGWEPPMLNFMGATMEQDLYQLAESVANVAEHQRKQEIKRLSTEHS
  SVSEYHPADGYAFSSNIYTRGSHLDQGEAAVAFKPTSNRHIDRNYEPLKTQPKKYAKSKY
  DFVARNNSELSVLKDDILEILDDRKQWWKVRNASGDSGFVPNNILDIVRPPESGLGRADP
  PYTHTIQKQRMEYGPRPADTPPAPSPPPTPAPVPVPLPPSTPAPVPVSKVPANITRQNSS
  SSDSGGSIVRDSQRHKQLPVDRRKSQMEEVQDELIHRLTIGRSAAQKKFHVPRQNVPVIN
  ITYDSTPEDVKTWLQSKGFNPVTVNSLGVLNGAQLFSLNKDELRTVCPEGARVYSQITVQ
  KAALEDSSGSSELQEIMRRRQEKISAAASDSGVESFDEGSSH
• Function: Signaling adapter that controls various cellular protrusions by regulating actin cytoskeleton dynamics and architecture. Depending on its association with other signal transducers, can regulate different processes. Together with SOS1 and ABI1, forms a trimeric complex that participates in transduction of signals from Ras to Rac by activating the Rac-specific guanine nucleotide exchange factor (GEF) activity. Acts as a direct regulator of actin dynamics by binding actin filaments and has both barbed-end actin filament capping and actin bundling activities depending on the context. Displays barbed-end actin capping activity when associated with ABI1, thereby regulating actin-based motility process: capping activity is auto-inhibited and inhibition is relieved upon ABI1 interaction. Also shows actin bundling activity when associated with BAIAP2, enhancing BAIAP2-dependent membrane extensions and promoting filopodial protrusions. Involved in the regulation of processes such as axonal filopodia growth, stereocilia length, dendritic cell migration and cancer cell migration and invasion. Acts as a regulator of axonal filopodia formation in neurons: in the absence of neurotrophic factors, negatively regulates axonal filopodia formation via actin-capping activity. In contrast, it is phosphorylated in the presence of BDNF leading to inhibition of its actin-capping activity and stimulation of filopodia formation. Component of a complex with WHRN and MYO15A that localizes at stereocilia tips and is required for elongation of the stereocilia actin core. Indirectly involved in cell cycle progression; its degradation following ubiquitination being required during G2 phase to promote cell shape changes.
• Tissue Specificity: Expressed in all tissues analyzed, including heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas. Expressed in all epithelial and fibroblastic lines examined and in some, but not all, hematopoietic cells.
• 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

42 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adenoma	DIS78ZEV	Definitive	Altered Expression	[1]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Definitive	Biomarker	[2]
Colon cancer	DISVC52G	Definitive	Altered Expression	[1]
Colon carcinoma	DISJYKUO	Definitive	Altered Expression	[1]
Colonic neoplasm	DISSZ04P	Definitive	Altered Expression	[1]
Colorectal adenoma	DISTSVHM	Definitive	Altered Expression	[1]
Colorectal carcinoma	DIS5PYL0	Definitive	Altered Expression	[1]
Invasive breast carcinoma	DISANYTW	Definitive	Altered Expression	[3]
Liver cancer	DISDE4BI	Definitive	Biomarker	[2]
Pancreatic ductal carcinoma	DIS26F9Q	Definitive	Biomarker	[4]
Acute myelogenous leukaemia	DISCSPTN	Strong	Altered Expression	[5]
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[6]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[7]
Autism spectrum disorder	DISXK8NV	Strong	Altered Expression	[8]
Autosomal recessive nonsyndromic hearing loss 102	DISAFFGJ	Strong	Autosomal recessive	[9]
Breast cancer	DIS7DPX1	Strong	Biomarker	[10]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[10]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[11]
Burkitt lymphoma	DIS9D5XU	Strong	Altered Expression	[12]
Carcinoma	DISH9F1N	Strong	Biomarker	[13]
Cholangiocarcinoma	DIS71F6X	Strong	Biomarker	[14]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[15]
Glioma	DIS5RPEH	Strong	Altered Expression	[16]
Malignant glioma	DISFXKOV	Strong	Biomarker	[16]
Matthew-Wood syndrome	DISA7HR7	Strong	Biomarker	[4]
Neoplasm	DISZKGEW	Strong	Biomarker	[10]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[17]
Squamous cell carcinoma	DISQVIFL	Strong	Altered Expression	[18]
Hearing loss, autosomal recessive	DIS8G9R9	Supportive	Autosomal recessive	[9]
Plasma cell myeloma	DIS0DFZ0	Disputed	Biomarker	[13]
Autism	DISV4V1Z	Limited	Altered Expression	[19]
Epithelial ovarian cancer	DIS56MH2	Limited	Biomarker	[20]
Head and neck cancer	DISBPSQZ	Limited	Altered Expression	[21]
Head and neck carcinoma	DISOU1DS	Limited	Altered Expression	[21]
Hepatocellular carcinoma	DIS0J828	Limited	Biomarker	[22]
Intellectual disability	DISMBNXP	Limited	Altered Expression	[19]
Lung cancer	DISCM4YA	Limited	Biomarker	[23]
Lung carcinoma	DISTR26C	Limited	Biomarker	[23]
Metastatic malignant neoplasm	DIS86UK6	Limited	Altered Expression	[21]
Ovarian cancer	DISZJHAP	Limited	Biomarker	[20]
Ovarian neoplasm	DISEAFTY	Limited	Biomarker	[20]
Pancreatic cancer	DISJC981	Limited	Biomarker	[24]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Capecitabine	DMTS85L	Approved	Epidermal growth factor receptor kinase substrate 8 (EPS8) increases the response to substance of Capecitabine.	[49]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Epidermal growth factor receptor kinase substrate 8 (EPS8).	[25]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Epidermal growth factor receptor kinase substrate 8 (EPS8).	[40]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Epidermal growth factor receptor kinase substrate 8 (EPS8).	[43]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Epidermal growth factor receptor kinase substrate 8 (EPS8).	[26]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Epidermal growth factor receptor kinase substrate 8 (EPS8).	[27]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Epidermal growth factor receptor kinase substrate 8 (EPS8).	[28]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Epidermal growth factor receptor kinase substrate 8 (EPS8).	[29]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Epidermal growth factor receptor kinase substrate 8 (EPS8).	[30]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Epidermal growth factor receptor kinase substrate 8 (EPS8).	[31]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Epidermal growth factor receptor kinase substrate 8 (EPS8).	[32]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Epidermal growth factor receptor kinase substrate 8 (EPS8).	[33]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Epidermal growth factor receptor kinase substrate 8 (EPS8).	[34]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Epidermal growth factor receptor kinase substrate 8 (EPS8).	[35]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Epidermal growth factor receptor kinase substrate 8 (EPS8).	[36]
Benzatropine	DMF7EXL	Approved	Benzatropine decreases the expression of Epidermal growth factor receptor kinase substrate 8 (EPS8).	[37]
Plicamycin	DM7C8YV	Approved	Plicamycin decreases the expression of Epidermal growth factor receptor kinase substrate 8 (EPS8).	[38]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Epidermal growth factor receptor kinase substrate 8 (EPS8).	[39]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Epidermal growth factor receptor kinase substrate 8 (EPS8).	[41]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Epidermal growth factor receptor kinase substrate 8 (EPS8).	[42]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Epidermal growth factor receptor kinase substrate 8 (EPS8).	[45]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Epidermal growth factor receptor kinase substrate 8 (EPS8).	[46]
4-hydroxy-2-nonenal	DM2LJFZ	Investigative	4-hydroxy-2-nonenal decreases the expression of Epidermal growth factor receptor kinase substrate 8 (EPS8).	[47]
Forskolin	DM6ITNG	Investigative	Forskolin decreases the expression of Epidermal growth factor receptor kinase substrate 8 (EPS8).	[48]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the localization of Epidermal growth factor receptor kinase substrate 8 (EPS8).	[44]

References

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• [2] Upregulation of EPS8L3 is associated with tumorigenesis and poor prognosis in patients with liver cancer.Mol Med Rep. 2019 Sep;20(3):2493-2499. doi: 10.3892/mmr.2019.10471. Epub 2019 Jul 4.
• [3] Eps8 regulates cellular proliferation and migration of breast cancer.Int J Oncol. 2015 Jan;46(1):205-14. doi: 10.3892/ijo.2014.2710. Epub 2014 Oct 17.
• [4] Gene regulation by antitumor miR-130b-5p in pancreatic ductal adenocarcinoma: the clinical significance of oncogenic EPS8.J Hum Genet. 2019 Jun;64(6):521-534. doi: 10.1038/s10038-019-0584-6. Epub 2019 Mar 11.
• [5] A synthetic cell-penetrating peptide derived from nuclear localization signal of EPS8 exerts anticancer activity against acute myeloid leukemia.J Exp Clin Cancer Res. 2018 Jan 22;37(1):12. doi: 10.1186/s13046-018-0682-x.
• [6] Silencing of Eps8 blocks migration and invasion in human glioblastoma cell lines.Exp Cell Res. 2012 Sep 10;318(15):1901-12. doi: 10.1016/j.yexcr.2012.05.010. Epub 2012 Jun 8.
• [7] Novel Nuclear Partnering Role of EPS8 With FOXM1 in Regulating Cell Proliferation.Front Oncol. 2019 Mar 19;9:154. doi: 10.3389/fonc.2019.00154. eCollection 2019.
• [8] Lack of the Actin Capping Protein, Eps8, Affects NMDA-Type Glutamate Receptor Function and Composition.Front Mol Neurosci. 2018 Sep 5;11:313. doi: 10.3389/fnmol.2018.00313. eCollection 2018.
• [9] EPS8, encoding an actin-binding protein of cochlear hair cell stereocilia, is a new causal gene for autosomal recessive profound deafness. Orphanet J Rare Dis. 2014 Apr 17;9:55. doi: 10.1186/1750-1172-9-55.
• [10] LncRNA DSCAM-AS1 acts as a sponge of miR-137 to enhance Tamoxifen resistance in breast cancer.J Cell Physiol. 2019 Mar;234(3):2880-2894. doi: 10.1002/jcp.27105. Epub 2018 Sep 10.
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• [14] Differential membrane proteomics using 18O-labeling to identify biomarkers for cholangiocarcinoma.J Proteome Res. 2008 Nov;7(11):4670-7. doi: 10.1021/pr800215n. Epub 2008 Oct 8.
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• [17] FoxO3a inhibiting expression of EPS8 to prevent progression of NSCLC: A new negative loop of EGFR signaling.EBioMedicine. 2019 Feb;40:198-209. doi: 10.1016/j.ebiom.2019.01.053. Epub 2019 Feb 7.
• [18] Expression of Eps8 correlates with poor survival in oral squamous cell carcinoma.Asia Pac J Clin Oncol. 2012 Dec;8(4):e77-81. doi: 10.1111/j.1743-7563.2011.01459.x. Epub 2012 Jan 12.
• [19] Eps8 controls dendritic spine density and synaptic plasticity through its actin-capping activity.EMBO J. 2013 Jun 12;32(12):1730-44. doi: 10.1038/emboj.2013.107. Epub 2013 May 17.
• [20] Integrity of SOS1/EPS8/ABI1 tri-complex determines ovarian cancer metastasis.Cancer Res. 2010 Dec 1;70(23):9979-90. doi: 10.1158/0008-5472.CAN-10-2394. Epub 2010 Nov 30.
• [21] Eps8 expression is significantly lower in p16(+) head and neck squamous cell carcinomas (HNSCCs) compared with p16(-) HNSCCs.Hum Pathol. 2018 Feb;72:45-51. doi: 10.1016/j.humpath.2017.10.021. Epub 2017 Oct 28.
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• [23] Intersectin-1s deficiency in pulmonary pathogenesis.Respir Res. 2017 Sep 6;18(1):168. doi: 10.1186/s12931-017-0652-4.
• [24] Comparative proteomic analysis identifies exosomal Eps8 protein as a potential metastatic biomarker for pancreatic cancer.Oncol Rep. 2019 Feb;41(2):1019-1034. doi: 10.3892/or.2018.6869. Epub 2018 Nov 15.
• [25] 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.
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• [27] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
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• [32] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
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• [34] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [35] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [36] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [37] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [38] Mithramycin inhibits human epithelial carcinoma cell proliferation and migration involving downregulation of Eps8 expression. Chem Biol Interact. 2010 Jan 5;183(1):181-6. doi: 10.1016/j.cbi.2009.09.018.
• [39] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [40] 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.
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• [42] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [43] 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.
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• [48] Drug development for ovarian hyper-stimulation and anti-cancer treatment: blocking of gonadotropin signaling for epiregulin and amphiregulin biosynthesis. Biochem Pharmacol. 2004 Sep 15;68(6):989-96. doi: 10.1016/j.bcp.2004.05.027.
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