Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTSOET5L)

• DOT Name: ELL-associated factor 2 (EAF2)
• Synonyms: Testosterone-regulated apoptosis inducer and tumor suppressor protein
• Gene Name: EAF2
• Related Disease:
  Attention deficit hyperactivity disorder
  Myocardial infarction
  Prostate neoplasm
  Advanced cancer
  Allergic rhinitis
  Autism
  B-cell neoplasm
  Hemochromatosis
  Hepatocellular carcinoma
  Lung adenocarcinoma
  Lung cancer
  Lung neoplasm
  Mental disorder
  Neoplasm
  Obesity
  Prostate cancer
  Retinoblastoma
  Acute myelogenous leukaemia
  Anxiety
  Anxiety disorder
  Asthma
  B-cell lymphoma
  Prostate carcinoma
  Venous thromboembolism
• UniProt ID: EAF2_HUMAN
• Pfam ID: PF09816
• Sequence:
  MNSAAGFSHLDRRERVLKLGESFEKQPRCAFHTVRYDFKPASIDTSSEGYLEVGEGEQVT
  ITLPNIEGSTPPVTVFKGSKKPYLKECILIINHDTGECRLEKLSSNITVKKTRVEGSSKI
  QYRKEQQQQQMWNSARTPNLVKHSPSEDKMSPASPIDDIERELKAEASLMDQMSSCDSSS
  DSKSSSSSSSEDSSSDSEDEDCKSSTSDTGNCVSGHPTMTQYRIPDIDASHNRFRDNSGL
  LMNTLRNDLQLSESGSDSDD
• Function: Acts as a transcriptional transactivator of TCEA1 elongation activity. Acts as a transcriptional transactivator of ELL and ELL2 elongation activities. Potent inducer of apoptosis in prostatic and non-prostatic cell lines. Inhibits prostate tumor growth in vivo.
• Tissue Specificity: Expressed in heart, brain, placenta, lung, skeletal muscle, kidney, pancreas, spleen, prostate, testis, small intestine, colon, adrenal, bone marrow, lymph node, spinal gland, stomach, thyroid, trachea, thymus, liver and leukocytes.
• Reactome Pathway:
  RNA Polymerase II Pre-transcription Events (R-HSA-674695)
  RNA Polymerase II Transcription Elongation (R-HSA-75955)
  Formation of RNA Pol II elongation complex (R-HSA-112382)

Molecular Interaction Atlas (MIA) of This DOT

24 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Attention deficit hyperactivity disorder	DISL8MX9	Definitive	Biomarker	[1]
Myocardial infarction	DIS655KI	Definitive	Genetic Variation	[2]
Prostate neoplasm	DISHDKGQ	Definitive	Biomarker	[3]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[4]
Allergic rhinitis	DIS3U9HN	Strong	Biomarker	[5]
Autism	DISV4V1Z	Strong	Biomarker	[6]
B-cell neoplasm	DISVY326	Strong	Biomarker	[7]
Hemochromatosis	DISAPY0H	Strong	Genetic Variation	[8]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[7]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[9]
Lung cancer	DISCM4YA	Strong	Biomarker	[7]
Lung neoplasm	DISVARNB	Strong	Biomarker	[7]
Mental disorder	DIS3J5R8	Strong	Biomarker	[10]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[11]
Obesity	DIS47Y1K	Strong	Biomarker	[12]
Prostate cancer	DISF190Y	Strong	Altered Expression	[3]
Retinoblastoma	DISVPNPB	Strong	Biomarker	[13]
Acute myelogenous leukaemia	DISCSPTN	Limited	Genetic Variation	[14]
Anxiety	DISIJDBA	Limited	Biomarker	[15]
Anxiety disorder	DISBI2BT	Limited	Biomarker	[15]
Asthma	DISW9QNS	Limited	Biomarker	[16]
B-cell lymphoma	DISIH1YQ	Limited	Biomarker	[17]
Prostate carcinoma	DISMJPLE	Limited	Altered Expression	[3]
Venous thromboembolism	DISUR7CR	Limited	Genetic Variation	[18]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Simvastatin	DM30SGU	Approved	ELL-associated factor 2 (EAF2) decreases the response to substance of Simvastatin.	[38]
Lovastatin	DM9OZWQ	Approved	ELL-associated factor 2 (EAF2) decreases the response to substance of Lovastatin.	[38]

24 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 ELL-associated factor 2 (EAF2).	[19]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of ELL-associated factor 2 (EAF2).	[20]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of ELL-associated factor 2 (EAF2).	[21]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of ELL-associated factor 2 (EAF2).	[22]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of ELL-associated factor 2 (EAF2).	[23]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of ELL-associated factor 2 (EAF2).	[24]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of ELL-associated factor 2 (EAF2).	[25]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of ELL-associated factor 2 (EAF2).	[7]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of ELL-associated factor 2 (EAF2).	[27]
Niclosamide	DMJAGXQ	Approved	Niclosamide decreases the expression of ELL-associated factor 2 (EAF2).	[28]
Docetaxel	DMDI269	Approved	Docetaxel decreases the expression of ELL-associated factor 2 (EAF2).	[27]
Dutasteride	DMQ4TJK	Approved	Dutasteride decreases the expression of ELL-associated factor 2 (EAF2).	[7]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of ELL-associated factor 2 (EAF2).	[29]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of ELL-associated factor 2 (EAF2).	[30]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of ELL-associated factor 2 (EAF2).	[31]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of ELL-associated factor 2 (EAF2).	[32]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of ELL-associated factor 2 (EAF2).	[33]
Scriptaid	DM9JZ21	Preclinical	Scriptaid increases the expression of ELL-associated factor 2 (EAF2).	[27]
Oxamflatin	DM1TG3C	Terminated	Oxamflatin increases the expression of ELL-associated factor 2 (EAF2).	[27]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of ELL-associated factor 2 (EAF2).	[35]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone increases the expression of ELL-associated factor 2 (EAF2).	[36]
cinnamaldehyde	DMZDUXG	Investigative	cinnamaldehyde decreases the expression of ELL-associated factor 2 (EAF2).	[37]
Apicidin	DM83WVF	Investigative	Apicidin increases the expression of ELL-associated factor 2 (EAF2).	[27]
Octanedioic acid bis-hydroxyamide	DMJNQ9K	Investigative	Octanedioic acid bis-hydroxyamide increases the expression of ELL-associated factor 2 (EAF2).	[27]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of ELL-associated factor 2 (EAF2).	[34]

References

• [1] The dopaminergic system in attention deficit/hyperactivity disorder.Congenit Anom (Kyoto). 2003 Jun;43(2):114-22. doi: 10.1111/j.1741-4520.2003.tb01035.x.
• [2] Parental history of myocardial infarction: lipid traits, gene polymorphisms and lifestyle.Atherosclerosis. 2001 Mar;155(1):149-56. doi: 10.1016/s0021-9150(00)00521-9.
• [3] Conditional Deletion of Eaf1 Induces Murine Prostatic Intraepithelial Neoplasia in Mice.Neoplasia. 2019 Aug;21(8):752-764. doi: 10.1016/j.neo.2019.05.005. Epub 2019 Jun 21.
• [4] Identification of a genetic interaction between the tumor suppressor EAF2 and the retinoblastoma protein (Rb) signaling pathway in C. elegans and prostate cancer cells.Biochem Biophys Res Commun. 2014 May 2;447(2):292-8. doi: 10.1016/j.bbrc.2014.03.138. Epub 2014 Apr 12.
• [5] Assessing patient-reported outcomes in asthma and COPD patients: which can be recommended in clinical practice?.Curr Opin Pulm Med. 2018 Jan;24(1):18-23. doi: 10.1097/MCP.0000000000000447.
• [6] Heritable genotype contrast mining reveals novel gene associations specific to autism subgroups.J Biomed Inform. 2018 Jan;77:50-61. doi: 10.1016/j.jbi.2017.11.016. Epub 2017 Nov 29.
• [7] Inhibition of 5alpha-reductase enhances testosterone-induced expression of U19/Eaf2 tumor suppressor during the regrowth of LNCaP xenograft tumor in nude mice. Prostate. 2010 Oct 1;70(14):1575-85. doi: 10.1002/pros.21193.
• [8] Genome-wide association study of iron traits and relation to diabetes in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL): potential genomic intersection of iron and glucose regulation?.Hum Mol Genet. 2017 May 15;26(10):1966-1978. doi: 10.1093/hmg/ddx082.
• [9] Development of a reactive stroma associated with prostatic intraepithelial neoplasia in EAF2 deficient mice.PLoS One. 2013 Nov 18;8(11):e79542. doi: 10.1371/journal.pone.0079542. eCollection 2013.
• [10] Discovering schizophrenia endophenotypes in randomly ascertained pedigrees.Biol Psychiatry. 2015 Jan 1;77(1):75-83. doi: 10.1016/j.biopsych.2014.06.027. Epub 2014 Jul 21.
• [11] EAF2 and p53 Co-Regulate STAT3 Activation in Prostate Cancer.Neoplasia. 2018 Apr;20(4):351-363. doi: 10.1016/j.neo.2018.01.011. Epub 2018 Mar 6.
• [12] Pleiotropy of cardiometabolic syndrome with obesity-related anthropometric traits determined using empirically derived kinships from the Busselton Health Study.Hum Genet. 2018 Jan;137(1):45-53. doi: 10.1007/s00439-017-1856-x. Epub 2017 Nov 27.
• [13] Physical and Functional Interactions between ELL2 and RB in the Suppression of Prostate Cancer Cell Proliferation, Migration, and Invasion.Neoplasia. 2017 Mar;19(3):207-215. doi: 10.1016/j.neo.2017.01.001. Epub 2017 Feb 3.
• [14] Apoptosis induction and growth suppression by U19/Eaf2 is mediated through its ELL-binding domain.Prostate. 2007 Feb 1;67(2):146-53. doi: 10.1002/pros.20481.
• [15] First genome-wide association study on anxiety-related behaviours in childhood.PLoS One. 2013;8(4):e58676. doi: 10.1371/journal.pone.0058676. Epub 2013 Apr 2.
• [16] Current and future targeted therapies for severe asthma: Managing treatment with biologics based on phenotypes and biomarkers.Pharmacol Res. 2019 Aug;146:104296. doi: 10.1016/j.phrs.2019.104296. Epub 2019 Jun 4.
• [17] FOXP1 directly represses transcription of proapoptotic genes and cooperates with NF-B to promote survival of human B cells.Blood. 2014 Nov 27;124(23):3431-40. doi: 10.1182/blood-2014-01-553412. Epub 2014 Sep 29.
• [18] Genomic and transcriptomic association studies identify 16 novel susceptibility loci for venous thromboembolism.Blood. 2019 Nov 7;134(19):1645-1657. doi: 10.1182/blood.2019000435.
• [19] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [20] 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.
• [21] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [22] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [23] 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.
• [24] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [25] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [26] Inhibition of 5alpha-reductase enhances testosterone-induced expression of U19/Eaf2 tumor suppressor during the regrowth of LNCaP xenograft tumor in nude mice. Prostate. 2010 Oct 1;70(14):1575-85. doi: 10.1002/pros.21193.
• [27] Development and validation of the TGx-HDACi transcriptomic biomarker to detect histone deacetylase inhibitors in human TK6 cells. Arch Toxicol. 2021 May;95(5):1631-1645. doi: 10.1007/s00204-021-03014-2. Epub 2021 Mar 26.
• [28] 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.
• [29] 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.
• [30] 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.
• [31] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [32] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [33] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [34] 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.
• [35] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [36] Gene expression signature-based chemical genomic prediction identifies a novel class of HSP90 pathway modulators. Cancer Cell. 2006 Oct;10(4):321-30.
• [37] Comparative DNA microarray analysis of human monocyte derived dendritic cells and MUTZ-3 cells exposed to the moderate skin sensitizer cinnamaldehyde. Toxicol Appl Pharmacol. 2009 Sep 15;239(3):273-83.
• [38] NCI60 cancer cell line panel data and RNAi analysis help identify EAF2 as a modulator of simvastatin and lovastatin response in HCT-116 cells. PLoS One. 2011 Apr 4;6(4):e18306. doi: 10.1371/journal.pone.0018306.