Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTV5LKIA)

• DOT Name: ETS-related transcription factor Elf-1 (ELF1)
• Synonyms: E74-like factor 1
• Gene Name: ELF1
• Related Disease:
  Cervical cancer
  Cervical carcinoma
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Chronic granulomatous disease
  Endometrial carcinoma
  Hepatitis C virus infection
  Hepatocellular carcinoma
  Inflammatory bowel disease
  Lupus
  Prostate cancer
  Prostate carcinoma
  Retinoblastoma
  Systemic lupus erythematosus
  Crohn disease
  Acute myelogenous leukaemia
  Nasopharyngeal carcinoma
  Neoplasm
• UniProt ID: ELF1_HUMAN
• Pfam ID: PF12310 ; PF00178
• Sequence:
  MAAVVQQNDLVFEFASNVMEDERQLGDPAIFPAVIVEHVPGADILNSYAGLACVEEPNDM
  ITESSLDVAEEEIIDDDDDDITLTVEASCHDGDETIETIEAAEALLNMDSPGPMLDEKRI
  NNNIFSSPEDDMVVAPVTHVSVTLDGIPEVMETQQVQEKYADSPGASSPEQPKRKKGRKT
  KPPRPDSPATTPNISVKKKNKDGKGNTIYLWEFLLALLQDKATCPKYIKWTQREKGIFKL
  VDSKAVSRLWGKHKNKPDMNYETMGRALRYYYQRGILAKVEGQRLVYQFKEMPKDLIYIN
  DEDPSSSIESSDPSLSSSATSNRNQTSRSRVSSSPGVKGGATTVLKPGNSKAAKPKDPVE
  VAQPSEVLRTVQPTQSPYPTQLFRTVHVVQPVQAVPEGEAARTSTMQDETLNSSVQSIRT
  IQAPTQVPVVVSPRNQQLHTVTLQTVPLTTVIASTDPSAGTGSQKFILQAIPSSQPMTVL
  KENVMLQSQKAGSPPSIVLGPAQVQQVLTSNVQTICNGTVSVASSPSFSATAPVVTFSPR
  SSQLVAHPPGTVITSVIKTQETKTLTQEVEKKESEDHLKENTEKTEQQPQPYVMVVSSSN
  GFTSQVAMKQNELLEPNSF
• Function: Transcription factor that activates the LYN and BLK promoters. Appears to be required for the T-cell-receptor-mediated trans activation of HIV-2 gene expression. Binds specifically to two purine-rich motifs in the HIV-2 enhancer.
• Tissue Specificity: In fetal tissues, it is highly expressed in heart, lung liver and kidney, and weakly expressed in brain. In adult, it is highly expressed in pancreas, spleen, thymus and peripheral blood leukocytes, expressed at moderate levels in heart, placenta, lung, liver, skeletal muscle, kidney, prostate, ovary, small intestine and colon, and weakly expressed in brain and testis.
• Reactome Pathway:
  RUNX1 regulates transcription of genes involved in interleukin signaling (R-HSA-8939247)
  RUNX1 regulates transcription of genes involved in BCR signaling (R-HSA-8939245)

Molecular Interaction Atlas (MIA) of This DOT

19 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cervical cancer	DISFSHPF	Definitive	Altered Expression	[1]
Cervical carcinoma	DIST4S00	Definitive	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[2]
Chronic granulomatous disease	DIS9ZR24	Strong	Genetic Variation	[3]
Endometrial carcinoma	DISXR5CY	Strong	Biomarker	[4]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[5]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[6]
Inflammatory bowel disease	DISGN23E	Strong	Genetic Variation	[7]
Lupus	DISOKJWA	Strong	Biomarker	[8]
Prostate cancer	DISF190Y	Strong	Altered Expression	[9]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[9]
Retinoblastoma	DISVPNPB	Strong	Biomarker	[1]
Systemic lupus erythematosus	DISI1SZ7	Strong	Genetic Variation	[10]
Crohn disease	DIS2C5Q8	moderate	Genetic Variation	[11]
Acute myelogenous leukaemia	DISCSPTN	Limited	Biomarker	[12]
Nasopharyngeal carcinoma	DISAOTQ0	Limited	Biomarker	[13]
Neoplasm	DISZKGEW	Limited	Altered Expression	[14]

21 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 ETS-related transcription factor Elf-1 (ELF1).	[15]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of ETS-related transcription factor Elf-1 (ELF1).	[16]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of ETS-related transcription factor Elf-1 (ELF1).	[17]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of ETS-related transcription factor Elf-1 (ELF1).	[18]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of ETS-related transcription factor Elf-1 (ELF1).	[19]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of ETS-related transcription factor Elf-1 (ELF1).	[20]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of ETS-related transcription factor Elf-1 (ELF1).	[21]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of ETS-related transcription factor Elf-1 (ELF1).	[23]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of ETS-related transcription factor Elf-1 (ELF1).	[24]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of ETS-related transcription factor Elf-1 (ELF1).	[24]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of ETS-related transcription factor Elf-1 (ELF1).	[25]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of ETS-related transcription factor Elf-1 (ELF1).	[26]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of ETS-related transcription factor Elf-1 (ELF1).	[27]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of ETS-related transcription factor Elf-1 (ELF1).	[28]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of ETS-related transcription factor Elf-1 (ELF1).	[29]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of ETS-related transcription factor Elf-1 (ELF1).	[30]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of ETS-related transcription factor Elf-1 (ELF1).	[33]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of ETS-related transcription factor Elf-1 (ELF1).	[34]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of ETS-related transcription factor Elf-1 (ELF1).	[35]
geraniol	DMS3CBD	Investigative	geraniol increases the expression of ETS-related transcription factor Elf-1 (ELF1).	[36]
Manganese	DMKT129	Investigative	Manganese decreases the expression of ETS-related transcription factor Elf-1 (ELF1).	[37]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide affects the methylation of ETS-related transcription factor Elf-1 (ELF1).	[22]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of ETS-related transcription factor Elf-1 (ELF1).	[31]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of ETS-related transcription factor Elf-1 (ELF1).	[32]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of ETS-related transcription factor Elf-1 (ELF1).	[32]

References

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• [2] Protein expression of the Ets transcription factor Elf-1 in breast cancer cells is negatively correlated with histological grading, but not with clinical outcome.Oncol Rep. 2011 Nov;26(5):1121-5. doi: 10.3892/or.2011.1409. Epub 2011 Aug 2.
• [3] Elf-1 and PU.1 induce expression of gp91(phox) via a promoter element mutated in a subset of chronic granulomatous disease patients.Blood. 1999 May 15;93(10):3512-20.
• [4] The relationship between oncogene expression and clinical outcome in endometrial carcinoma.Curr Cancer Drug Targets. 2004 Sep;4(6):511-20. doi: 10.2174/1568009043332871.
• [5] Detection of hepatitis C virus antibody in the absence of viral RNA in patients with autoimmune hepatitis.Ann Intern Med. 1992 Jan 1;116(1):21-5. doi: 10.7326/0003-4819-116-1-21.
• [6] Loss of cooperative function of transforming growth factor-beta signaling proteins, smad3 with embryonic liver fodrin, a beta-spectrin, in primary biliary cirrhosis.Liver Int. 2004 Dec;24(6):637-45. doi: 10.1111/j.1478-3231.2004.0958.x.
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• [8] PP2A dephosphorylates Elf-1 and determines the expression of CD3zeta and FcRgamma in human systemic lupus erythematosus T cells.J Immunol. 2008 Sep 1;181(5):3658-64. doi: 10.4049/jimmunol.181.5.3658.
• [9] Electrostatic repulsion causes anticooperative DNA binding between tumor suppressor ETS transcription factors and JUN-FOS at composite DNA sites.J Biol Chem. 2018 Nov 30;293(48):18624-18635. doi: 10.1074/jbc.RA118.003352. Epub 2018 Oct 12.
• [10] ELF1 is associated with systemic lupus erythematosus in Asian populations.Hum Mol Genet. 2011 Feb 1;20(3):601-7. doi: 10.1093/hmg/ddq474. Epub 2010 Nov 2.
• [11] A genome-wide association study identifies 2 susceptibility Loci for Crohn's disease in a Japanese population.Gastroenterology. 2013 Apr;144(4):781-8. doi: 10.1053/j.gastro.2012.12.021. Epub 2012 Dec 22.
• [12] The level of MEF but not ELF-1 correlates with FAB subtype of acute myeloid leukemia and is low in good prognosis cases.Leuk Res. 2003 May;27(5):387-92. doi: 10.1016/s0145-2126(02)00214-x.
• [13] ELF-1 expression in nasopharyngeal carcinoma facilitates proliferation and metastasis of cancer cells via modulation of CCL2/CCR2 signaling.Cancer Manag Res. 2019 Jun 6;11:5243-5254. doi: 10.2147/CMAR.S196355. eCollection 2019.
• [14] Ets protein Elf-1 bidirectionally suppresses transcriptional activities of the tumor suppressor Tsc2 gene and the repair-related Nth1 gene.Mol Carcinog. 2003 Jul;37(3):122-9. doi: 10.1002/mc.10123.
• [15] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [16] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [17] 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.
• [18] 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.
• [19] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [20] 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.
• [21] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [22] Analysis of the transcriptional regulation of cancer-related genes by aberrant DNA methylation of the cis-regulation sites in the promoter region during hepatocyte carcinogenesis caused by arsenic. Oncotarget. 2015 Aug 28;6(25):21493-506. doi: 10.18632/oncotarget.4085.
• [23] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [24] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [25] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [26] 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.
• [27] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [28] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [29] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [30] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [31] 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.
• [32] 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.
• [33] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [34] Chemical stresses fail to mimic the unfolded protein response resulting from luminal load with unfolded polypeptides. J Biol Chem. 2018 Apr 13;293(15):5600-5612.
• [35] 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.
• [36] Geraniol suppresses prostate cancer growth through down-regulation of E2F8. Cancer Med. 2016 Oct;5(10):2899-2908.
• [37] 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.