Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4R3ECK)

• DOT Name: Early growth response protein 4 (EGR4)
• Synonyms: EGR-4; AT133
• Gene Name: EGR4
• Related Disease:
  Breast carcinoma
  Cryptorchidism
  Leydig cell hypoplasia, type 1
  Male infertility
  Neoplasm
  Non-small-cell lung cancer
  Oligospermia
  Pituitary gland disorder
  Schizophrenia
  Small-cell lung cancer
• UniProt ID: EGR4_HUMAN
• Pfam ID: PF00096
• Sequence:
  MAVARGVGSPEPAPPQLYKWGGCGLGEPGSALERRGAAARGRCGRARAPRLPDSFPRGEC
  PKPGARAPRSVRCGEPLPPASPPPARPQAQRARPRAPHSRRRAMLHLSEFSEPDALLVKS
  TEGCCAEPSAELPRLPARDAPAATGYPGAGDFLSWALNSCGASGDLADSCFLEGPAPTPP
  PGLSYSGSFFIQAVPEHPHDPEALFNLMSGILGLAPFPGPEAAASRSPLDAPFPAGSDAL
  LPGPPDLYSPDLGAAPFPEAFWEASPCAGAPSQCLYEPQLSPPDVKPGLRAPPASPALDA
  VSAFKGPYAPWELLSVGAPGNCGSQGDYQAAPEARFPVIGTKIEDLLSISCPAELPAVPA
  NRLYPSGAYDAFPLAPGDLGEGAEGLPGLLTPPSGEGGSSGDGGEFLASTQPQLSPLGLR
  SAAAADFPKPLVADIPGSSGVAAPPVPPPPPTPFPQAKARRKGRRGGKCSTRCFCPRPHA
  KAFACPVESCVRSFARSDELNRHLRIHTGHKPFQCRICLRNFSRSDHLTTHVRTHTGEKP
  FACDVCGRRFARSDEKKRHSKVHLKQKARAEERLKGLGFYSLGLSFASL
• Function: Transcriptional regulator. Recognizes and binds to the DNA sequence 5'-GCGGGGGCG-3' (GSG). Activates the transcription of target genes whose products are required for mitogenesis and differentiation.
• Reactome Pathway: NGF-stimulated transcription (R-HSA-9031628)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast carcinoma	DIS2UE88	Strong	Biomarker	[1]
Cryptorchidism	DISYUD2P	Strong	Biomarker	[2]
Leydig cell hypoplasia, type 1	DISIX1DZ	Strong	Biomarker	[2]
Male infertility	DISY3YZZ	Strong	Genetic Variation	[3]
Neoplasm	DISZKGEW	Strong	Biomarker	[4]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[4]
Oligospermia	DIS6YJF3	Strong	Biomarker	[5]
Pituitary gland disorder	DIS7XB48	Strong	Biomarker	[6]
Schizophrenia	DISSRV2N	Strong	Biomarker	[7]
Small-cell lung cancer	DISK3LZD	moderate	Biomarker	[8]

13 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 Early growth response protein 4 (EGR4).	[9]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Early growth response protein 4 (EGR4).	[10]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Early growth response protein 4 (EGR4).	[11]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Early growth response protein 4 (EGR4).	[12]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Early growth response protein 4 (EGR4).	[13]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Early growth response protein 4 (EGR4).	[14]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Early growth response protein 4 (EGR4).	[15]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Early growth response protein 4 (EGR4).	[16]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Early growth response protein 4 (EGR4).	[17]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Early growth response protein 4 (EGR4).	[18]
Aspirin	DM672AH	Approved	Aspirin decreases the expression of Early growth response protein 4 (EGR4).	[20]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Early growth response protein 4 (EGR4).	[21]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Early growth response protein 4 (EGR4).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Early growth response protein 4 (EGR4).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Early growth response protein 4 (EGR4).	[22]

References

• [1] Expression and prognostic analyses of early growth response proteins (EGRs) in human breast carcinoma based on database analysis.PeerJ. 2019 Dec 9;7:e8183. doi: 10.7717/peerj.8183. eCollection 2019.
• [2] Molecular Pathology of Cryptorchidism-Induced Infertility.Sex Dev. 2015;9(5):269-78. doi: 10.1159/000442059. Epub 2015 Dec 8.
• [3] Sequence variations of the EGR4 gene in Korean men with spermatogenesis impairment.BMC Med Genet. 2017 May 2;18(1):47. doi: 10.1186/s12881-017-0408-5.
• [4] A positive feedback loop between ZNF205-AS1 and EGR4 promotes non-small cell lung cancer growth.J Cell Mol Med. 2019 Feb;23(2):1495-1508. doi: 10.1111/jcmm.14056. Epub 2018 Dec 16.
• [5] Infertility associated with incomplete spermatogenic arrest and oligozoospermia in Egr4-deficient mice.Development. 1999 Nov;126(22):5061-71. doi: 10.1242/dev.126.22.5061.
• [6] EGR4 is a master gene responsible for fertility in cryptorchidism.Sex Dev. 2009;3(5):253-63. doi: 10.1159/000249147. Epub 2009 Oct 14.
• [7] Genetic and functional analyses of early growth response (EGR) family genes in schizophrenia.Prog Neuropsychopharmacol Biol Psychiatry. 2012 Oct 1;39(1):149-55. doi: 10.1016/j.pnpbp.2012.06.004. Epub 2012 Jun 9.
• [8] Early growth response 4 is involved in cell proliferation of small cell lung cancer through transcriptional activation of its downstream genes.PLoS One. 2014 Nov 20;9(11):e113606. doi: 10.1371/journal.pone.0113606. eCollection 2014.
• [9] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [10] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [11] 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.
• [12] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [13] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [18] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [19] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [20] Expression profile analysis of colon cancer cells in response to sulindac or aspirin. Biochem Biophys Res Commun. 2002 Mar 29;292(2):498-512.
• [21] 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.
• [22] 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.
• [23] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.