Details of Drug Off-Target (DOT)

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

• DOT Name: ETS domain-containing protein Elk-4 (ELK4)
• Synonyms: Serum response factor accessory protein 1; SAP-1; SRF accessory protein 1
• Gene Name: ELK4
• Related Disease:
  Adult glioblastoma
  Glioblastoma multiforme
  Glioma
  Candidiasis
  Colitis
  Gastric cancer
  Hepatitis B virus infection
  HIV infectious disease
  Inflammatory bowel disease
  Oral candidiasis
  Progressive multifocal leukoencephalopathy
  Prostate neoplasm
  Stomach cancer
  Vaginal infection
  Metachromatic leukodystrophy
  Vulvovaginal Candidiasis
  Malaria
  Breast cancer
  Breast carcinoma
  Colorectal carcinoma
  Melanoma
  Neoplasm
• UniProt ID: ELK4_HUMAN
• PDB ID: 1BC7; 1BC8; 1HBX; 1K6O
• Pfam ID: PF00178
• Sequence:
  MDSAITLWQFLLQLLQKPQNKHMICWTSNDGQFKLLQAEEVARLWGIRKNKPNMNYDKLS
  RALRYYYVKNIIKKVNGQKFVYKFVSYPEILNMDPMTVGRIEGDCESLNFSEVSSSSKDV
  ENGGKDKPPQPGAKTSSRNDYIHSGLYSSFTLNSLNSSNVKLFKLIKTENPAEKLAEKKS
  PQEPTPSVIKFVTTPSKKPPVEPVAATISIGPSISPSSEETIQALETLVSPKLPSLEAPT
  SASNVMTAFATTPPISSIPPLQEPPRTPSPPLSSHPDIDTDIDSVASQPMELPENLSLEP
  KDQDSVLLEKDKVNNSSRSKKPKGLELAPTLVITSSDPSPLGILSPSLPTASLTPAFFSQ
  TPIILTPSPLLSSIHFWSTLSPVAPLSPARLQGANTLFQFPSVLNSHGPFTLSGLDGPST
  PGPFSPDLQKT
• Function: Involved in both transcriptional activation and repression. Interaction with SIRT7 leads to recruitment and stabilization of SIRT7 at promoters, followed by deacetylation of histone H3 at 'Lys-18' (H3K18Ac) and subsequent transcription repression. Forms a ternary complex with the serum response factor (SRF). Requires DNA-bound SRF for ternary complex formation and makes extensive DNA contacts to the 5'side of SRF, but does not bind DNA autonomously.
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  Human T-cell leukemia virus 1 infection (hsa05166)
  Transcriptio.l misregulation in cancer (hsa05202)

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Definitive	Altered Expression	[1]
Glioblastoma multiforme	DISK8246	Definitive	Altered Expression	[1]
Glioma	DIS5RPEH	Definitive	Biomarker	[1]
Candidiasis	DISIRYMU	Strong	Altered Expression	[2]
Colitis	DISAF7DD	Strong	Biomarker	[3]
Gastric cancer	DISXGOUK	Strong	Biomarker	[4]
Hepatitis B virus infection	DISLQ2XY	Strong	Biomarker	[5]
HIV infectious disease	DISO97HC	Strong	Biomarker	[6]
Inflammatory bowel disease	DISGN23E	Strong	Biomarker	[3]
Oral candidiasis	DISAVKAH	Strong	Biomarker	[7]
Progressive multifocal leukoencephalopathy	DISX02WS	Strong	Biomarker	[8]
Prostate neoplasm	DISHDKGQ	Strong	Altered Expression	[9]
Stomach cancer	DISKIJSX	Strong	Biomarker	[4]
Vaginal infection	DISVXFB7	Strong	Biomarker	[10]
Metachromatic leukodystrophy	DIS3OMWS	moderate	Biomarker	[11]
Vulvovaginal Candidiasis	DISRCR6D	moderate	Biomarker	[12]
Malaria	DISQ9Y50	Disputed	Genetic Variation	[13]
Breast cancer	DIS7DPX1	Limited	Altered Expression	[14]
Breast carcinoma	DIS2UE88	Limited	Altered Expression	[14]
Colorectal carcinoma	DIS5PYL0	Limited	Altered Expression	[15]
Melanoma	DIS1RRCY	Limited	Altered Expression	[16]
Neoplasm	DISZKGEW	Limited	Altered Expression	[17]

23 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 ETS domain-containing protein Elk-4 (ELK4).	[18]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of ETS domain-containing protein Elk-4 (ELK4).	[19]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of ETS domain-containing protein Elk-4 (ELK4).	[20]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of ETS domain-containing protein Elk-4 (ELK4).	[21]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of ETS domain-containing protein Elk-4 (ELK4).	[22]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of ETS domain-containing protein Elk-4 (ELK4).	[23]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of ETS domain-containing protein Elk-4 (ELK4).	[24]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of ETS domain-containing protein Elk-4 (ELK4).	[26]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone increases the expression of ETS domain-containing protein Elk-4 (ELK4).	[22]
Cidofovir	DMA13GD	Approved	Cidofovir decreases the expression of ETS domain-containing protein Elk-4 (ELK4).	[22]
Fenofibrate	DMFKXDY	Approved	Fenofibrate increases the expression of ETS domain-containing protein Elk-4 (ELK4).	[22]
Ifosfamide	DMCT3I8	Approved	Ifosfamide decreases the expression of ETS domain-containing protein Elk-4 (ELK4).	[22]
Clodronate	DM9Y6X7	Approved	Clodronate decreases the expression of ETS domain-containing protein Elk-4 (ELK4).	[22]
Ibuprofen	DM8VCBE	Approved	Ibuprofen increases the expression of ETS domain-containing protein Elk-4 (ELK4).	[22]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of ETS domain-containing protein Elk-4 (ELK4).	[27]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of ETS domain-containing protein Elk-4 (ELK4).	[28]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of ETS domain-containing protein Elk-4 (ELK4).	[30]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of ETS domain-containing protein Elk-4 (ELK4).	[31]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of ETS domain-containing protein Elk-4 (ELK4).	[32]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of ETS domain-containing protein Elk-4 (ELK4).	[33]
geraniol	DMS3CBD	Investigative	geraniol increases the expression of ETS domain-containing protein Elk-4 (ELK4).	[34]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone increases the expression of ETS domain-containing protein Elk-4 (ELK4).	[35]
crotylaldehyde	DMTWRQI	Investigative	crotylaldehyde decreases the expression of ETS domain-containing protein Elk-4 (ELK4).	[36]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the methylation of ETS domain-containing protein Elk-4 (ELK4).	[25]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of ETS domain-containing protein Elk-4 (ELK4).	[29]

References

• [1] ELK4 neutralization sensitizes glioblastoma to apoptosis through downregulation of the anti-apoptotic protein Mcl-1.Neuro Oncol. 2011 Nov;13(11):1202-12. doi: 10.1093/neuonc/nor119. Epub 2011 Aug 16.
• [2] Quantitative expression of the Candida albicans secreted aspartyl proteinase gene family in human oral and vaginal candidiasis.Microbiology (Reading). 2008 Nov;154(Pt 11):3266-3280. doi: 10.1099/mic.0.2008/022293-0.
• [3] Protein tyrosine phosphatase SAP-1 protects against colitis through regulation of CEACAM20 in the intestinal epithelium.Proc Natl Acad Sci U S A. 2015 Aug 4;112(31):E4264-71. doi: 10.1073/pnas.1510167112. Epub 2015 Jul 20.
• [4] Molecular cloning of a human transmembrane-type protein tyrosine phosphatase and its expression in gastrointestinal cancers.J Biol Chem. 1994 Jan 21;269(3):2075-81.
• [5] Replication of clinical hepatitis B virus isolate and its application for selecting antiviral agents for chronic hepatitis B patients.World J Gastroenterol. 2008 Jun 14;14(22):3490-6. doi: 10.3748/wjg.14.3490.
• [6] Elevated aspartic proteinase secretion and experimental pathogenicity of Candida albicans isolates from oral cavities of subjects infected with human immunodeficiency virus.Infect Immun. 1996 Feb;64(2):466-71. doi: 10.1128/iai.64.2.466-471.1996.
• [7] In vivo analysis of secreted aspartyl proteinase expression in human oral candidiasis.Infect Immun. 1999 May;67(5):2482-90. doi: 10.1128/IAI.67.5.2482-2490.1999.
• [8] Molecular characterization of a JC virus (Sap-1) clone derived from a cerebellar form of progressive multifocal leukoencephalopathy.Acta Neuropathol. 1992;83(2):105-12. doi: 10.1007/BF00308469.
• [9] A variant of the KLK4 gene is expressed as a cis sense-antisense chimeric transcript in prostate cancer cells.RNA. 2010 Jun;16(6):1156-66. doi: 10.1261/rna.2019810. Epub 2010 Apr 20.
• [10] The secreted aspartyl proteinases Sap1 and Sap2 cause tissue damage in an in vitro model of vaginal candidiasis based on reconstituted human vaginal epithelium.Infect Immun. 2003 Jun;71(6):3227-34. doi: 10.1128/IAI.71.6.3227-3234.2003.
• [11] The mechanism for a 33-nucleotide insertion in mRNA causing sphingolipid activator protein (SAP-1)-deficient metachromatic leukodystrophy.Hum Genet. 1991 Jun;87(2):211-5. doi: 10.1007/BF00204185.
• [12] Differential expression of Candida albicans secreted aspartyl proteinase in human vulvovaginal candidiasis.Mycoses. 2007 Sep;50(5):383-90. doi: 10.1111/j.1439-0507.2007.01384.x.
• [13] Targeted deletion of SAP1 abolishes the expression of infectivity factors necessary for successful malaria parasite liver infection.Mol Microbiol. 2008 Jul;69(1):152-63. doi: 10.1111/j.1365-2958.2008.06271.x. Epub 2008 May 5.
• [14] Frequent copy number gains at 1q21 and 1q32 are associated with overexpression of the ETS transcription factors ETV3 and ELF3 in breast cancer irrespective of molecular subtypes.Breast Cancer Res Treat. 2013 Feb;138(1):37-45. doi: 10.1007/s10549-013-2408-2. Epub 2013 Jan 18.
• [15] MicroRNA-related transcription factor regulatory networks in human colorectal cancer.Medicine (Baltimore). 2019 Apr;98(15):e15158. doi: 10.1097/MD.0000000000015158.
• [16] Cyclin-dependent kinase 2 (CDK2) is a key mediator for EGF-induced cell transformation mediated through the ELK4/c-Fos signaling pathway.Oncogene. 2016 Mar 3;35(9):1170-9. doi: 10.1038/onc.2015.175. Epub 2015 Jun 1.
• [17] The ternary complex factor protein ELK1 is an independent prognosticator of disease recurrence in prostate cancer.Prostate. 2020 Feb;80(2):198-208. doi: 10.1002/pros.23932. Epub 2019 Dec 3.
• [18] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [19] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [20] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [21] 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.
• [22] Transcriptomics hit the target: monitoring of ligand-activated and stress response pathways for chemical testing. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):7-18.
• [23] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [24] 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.
• [25] 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.
• [26] 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.
• [27] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [28] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [29] 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.
• [30] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [31] 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.
• [32] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [33] Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.
• [34] Geraniol suppresses prostate cancer growth through down-regulation of E2F8. Cancer Med. 2016 Oct;5(10):2899-2908.
• [35] Acyl derivatives of p-aminosulfonamides and dapsone as new inhibitors of the arginine methyltransferase hPRMT1. Bioorg Med Chem. 2011 Jun 15;19(12):3717-31. doi: 10.1016/j.bmc.2011.02.032. Epub 2011 Feb 27.
• [36] Gene expression profile and cytotoxicity of human bronchial epithelial cells exposed to crotonaldehyde. Toxicol Lett. 2010 Aug 16;197(2):113-22.