Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLM94BI)

• DOT Name: Transcription factor NF-E2 45 kDa subunit (NFE2)
• Synonyms: Leucine zipper protein NF-E2; Nuclear factor, erythroid-derived 2 45 kDa subunit; p45 NF-E2
• Gene Name: NFE2
• Related Disease:
  Acute erythroid leukemia
  Acute monocytic leukemia
  Acute myelogenous leukaemia
  Advanced cancer
  Alcoholic liver diseases
  Anemia
  Arteriosclerosis
  Atherosclerosis
  Depression
  Epithelial ovarian cancer
  Immunodeficiency
  Intestinal neoplasm
  Legionnaires' disease
  Leukemia
  Liver cirrhosis
  Myelofibrosis
  Myeloproliferative neoplasm
  Neoplasm
  Non-small-cell lung cancer
  Ovarian cancer
  Ovarian neoplasm
  Pancreatic cancer
  Parkinson disease
  Polycythemia
  Primary myelofibrosis
  Secondary polycythemia
  Thrombocytopenia
  Vitiligo
  Essential thrombocythemia
  Thrombocytosis disease
  Hyperglycemia
  Pulmonary emphysema
• UniProt ID: NFE2_HUMAN
• PDB ID: 2KZ5
• Pfam ID: PF03131
• Sequence:
  MSPCPPQQSRNRVIQLSTSELGEMELTWQEIMSITELQGLNAPSEPSFEPQAPAPYLGPP
  PPTTYCPCSIHPDSGFPLPPPPYELPASTSHVPDPPYSYGNMAIPVSKPLSLSGLLSEPL
  QDPLALLDIGLPAGPPKPQEDPESDSGLSLNYSDAESLELEGTEAGRRRSEYVEMYPVEY
  PYSLMPNSLAHSNYTLPAAETPLALEPSSGPVRAKPTARGEAGSRDERRALAMKIPFPTD
  KIVNLPVDDFNELLARYPLTESQLALVRDIRRRGKNKVAAQNCRKRKLETIVQLERELER
  LTNERERLLRARGEADRTLEVMRQQLTELYRDIFQHLRDESGNSYSPEEYALQQAADGTI
  FLVPRGTKMEATD
• Function: Component of the NF-E2 complex essential for regulating erythroid and megakaryocytic maturation and differentiation. Binds to the hypersensitive site 2 (HS2) of the beta-globin control region (LCR). This subunit (NFE2) recognizes the TCAT/C sequence of the AP-1-like core palindrome present in a number of erythroid and megakaryocytic gene promoters. Requires MAFK or other small MAF proteins for binding to the NF-E2 motif. May play a role in all aspects of hemoglobin production from globin and heme synthesis to procurement of iron.
• Tissue Specificity: Expressed in hematopoietic cells and also in colon and testis.
• Reactome Pathway:
  Factors involved in megakaryocyte development and platelet production (R-HSA-983231)
  RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function (R-HSA-8936459)

Molecular Interaction Atlas (MIA) of This DOT

32 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute erythroid leukemia	DISZFC1O	Strong	Biomarker	[1]
Acute monocytic leukemia	DIS28NEL	Strong	Altered Expression	[2]
Acute myelogenous leukaemia	DISCSPTN	Strong	Genetic Variation	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Alcoholic liver diseases	DISXEPHQ	Strong	Biomarker	[4]
Anemia	DISTVL0C	Strong	Altered Expression	[5]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[6]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[6]
Depression	DIS3XJ69	Strong	Biomarker	[7]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[8]
Immunodeficiency	DIS093I0	Strong	Altered Expression	[9]
Intestinal neoplasm	DISK0GUH	Strong	Altered Expression	[10]
Legionnaires' disease	DIS8V4GQ	Strong	Biomarker	[11]
Leukemia	DISNAKFL	Strong	Genetic Variation	[2]
Liver cirrhosis	DIS4G1GX	Strong	Biomarker	[4]
Myelofibrosis	DISIMP21	Strong	Biomarker	[5]
Myeloproliferative neoplasm	DIS5KAPA	Strong	Altered Expression	[12]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[2]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[13]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[8]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[8]
Pancreatic cancer	DISJC981	Strong	Altered Expression	[14]
Parkinson disease	DISQVHKL	Strong	Biomarker	[15]
Polycythemia	DIS8B6VW	Strong	Altered Expression	[16]
Primary myelofibrosis	DIS6L0CN	Strong	Biomarker	[5]
Secondary polycythemia	DISKEVNK	Strong	Genetic Variation	[17]
Thrombocytopenia	DISU61YW	Strong	Genetic Variation	[18]
Vitiligo	DISR05SL	Strong	Altered Expression	[19]
Essential thrombocythemia	DISWWK11	moderate	Biomarker	[5]
Thrombocytosis disease	DISNG0P4	moderate	Altered Expression	[5]
Hyperglycemia	DIS0BZB5	Disputed	Altered Expression	[20]
Pulmonary emphysema	DIS5M7HZ	Limited	Altered Expression	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Transcription factor NF-E2 45 kDa subunit (NFE2).	[22]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Transcription factor NF-E2 45 kDa subunit (NFE2).	[23]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Transcription factor NF-E2 45 kDa subunit (NFE2).	[24]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Transcription factor NF-E2 45 kDa subunit (NFE2).	[25]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Transcription factor NF-E2 45 kDa subunit (NFE2).	[26]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Transcription factor NF-E2 45 kDa subunit (NFE2).	[24]
Zidovudine	DM4KI7O	Approved	Zidovudine decreases the expression of Transcription factor NF-E2 45 kDa subunit (NFE2).	[27]
Pomalidomide	DMTGBAX	Approved	Pomalidomide decreases the expression of Transcription factor NF-E2 45 kDa subunit (NFE2).	[28]
Aclarubicin	DMLFZHD	Approved	Aclarubicin increases the expression of Transcription factor NF-E2 45 kDa subunit (NFE2).	[29]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Transcription factor NF-E2 45 kDa subunit (NFE2).	[30]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Transcription factor NF-E2 45 kDa subunit (NFE2).	[31]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene increases the expression of Transcription factor NF-E2 45 kDa subunit (NFE2).	[22]
OTX-015	DMI8RG1	Phase 1/2	OTX-015 decreases the expression of Transcription factor NF-E2 45 kDa subunit (NFE2).	[32]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Transcription factor NF-E2 45 kDa subunit (NFE2).	[33]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Transcription factor NF-E2 45 kDa subunit (NFE2).	[34]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Transcription factor NF-E2 45 kDa subunit (NFE2).	[35]
Mivebresib	DMCPF90	Phase 1	Mivebresib decreases the expression of Transcription factor NF-E2 45 kDa subunit (NFE2).	[32]
Butanoic acid	DMTAJP7	Investigative	Butanoic acid increases the expression of Transcription factor NF-E2 45 kDa subunit (NFE2).	[29]
Protoporphyrin IX	DMWYE7A	Investigative	Protoporphyrin IX increases the expression of Transcription factor NF-E2 45 kDa subunit (NFE2).	[36]
Catechol	DML0YEK	Investigative	Catechol increases the expression of Transcription factor NF-E2 45 kDa subunit (NFE2).	[37]
Chebulinic acid	DMR8HKC	Investigative	Chebulinic acid decreases the expression of Transcription factor NF-E2 45 kDa subunit (NFE2).	[38]

References

• [1] Identification of a Novel Enhancer/Chromatin Opening Element Associated with High-Level -Globin Gene Expression.Mol Cell Biol. 2018 Sep 14;38(19):e00197-18. doi: 10.1128/MCB.00197-18. Print 2018 Oct 1.
• [2] Altered NFE2 activity predisposes to leukemic transformation and myelosarcoma with AML-specific aberrations.Blood. 2019 Apr 18;133(16):1766-1777. doi: 10.1182/blood-2018-09-875047. Epub 2019 Feb 12.
• [3] ERK and PI3K signaling cascades induce Nrf2 activation and regulate cell viability partly through Nrf2 in human glioblastoma cells.Oncol Rep. 2013 Aug;30(2):715-22. doi: 10.3892/or.2013.2485. Epub 2013 May 23.
• [4] Molecular genetic aspects of alcohol metabolism and alcoholism.Pharmacopsychiatry. 1997 May;30(3):79-84. doi: 10.1055/s-2007-979487.
• [5] A role of NF-E2 in chronic inflammation and clonal evolution in essential thrombocythemia, polycythemia vera and myelofibrosis?.Leuk Res. 2014 Feb;38(2):263-6. doi: 10.1016/j.leukres.2013.07.002. Epub 2013 Aug 9.
• [6] Treatment with apo B peptide vaccines inhibits atherosclerosis in human apo B-100 transgenic mice without inducing an increase in peptide-specific antibodies.J Intern Med. 2008 Dec;264(6):563-70. doi: 10.1111/j.1365-2796.2008.01995.x. Epub 2008 Sep 6.
• [7] Repetitive Passive Finger Movement Modulates Primary Somatosensory Cortex Excitability.Front Hum Neurosci. 2018 Aug 20;12:332. doi: 10.3389/fnhum.2018.00332. eCollection 2018.
• [8] Nrf2 induces cisplatin resistance via suppressing the iron export related gene SLC40A1 in ovarian cancer cells.Oncotarget. 2017 Jul 25;8(55):93502-93515. doi: 10.18632/oncotarget.19548. eCollection 2017 Nov 7.
• [9] Nuclear Factor Erythroid 2 Regulates Human HSC Self-Renewal and T Cell Differentiation by Preventing NOTCH1 Activation.Stem Cell Reports. 2017 Jul 11;9(1):5-11. doi: 10.1016/j.stemcr.2017.05.027. Epub 2017 Jun 22.
• [10] Activation of NF-E2 p45-related factor-2 transcription and inhibition of intestinal tumor development by AHCC, a standardized extract of cultured Lentinula edodes mycelia.J Clin Biochem Nutr. 2019 Nov;65(3):203-208. doi: 10.3164/jcbn.19-36. Epub 2019 Sep 27.
• [11] Legionnaires' Disease Mortality in Guinea Pigs Involves the p45 Mobile Genomic Element.J Infect Dis. 2019 Oct 8;220(10):1700-1710. doi: 10.1093/infdis/jiz340.
• [12] Epigenetic regulation of NFE2 overexpression in myeloproliferative neoplasms.Blood. 2018 May 3;131(18):2065-2073. doi: 10.1182/blood-2017-10-810622. Epub 2018 Mar 8.
• [13] Molecular mechanisms for the regulation of Nrf2-mediated cell proliferation in non-small-cell lung cancers.Oncogene. 2012 Nov 8;31(45):4768-77. doi: 10.1038/onc.2011.628. Epub 2012 Jan 16.
• [14] MBD1 is an Epigenetic Regulator of KEAP1 in Pancreatic Cancer.Curr Mol Med. 2016;16(4):404-11. doi: 10.2174/1566524016666160316154150.
• [15] The Neuroprotective Effect of Dimethyl Fumarate in an MPTP-Mouse Model of Parkinson's Disease: Involvement of Reactive Oxygen Species/Nuclear Factor-kB/Nuclear Transcription Factor Related to NF-E2. Antioxid Redox Signal. 2017 Sep 10;27(8):453-471.
• [16] RUNX1 and NF-E2 upregulation is not specific for MPNs, but is seen in polycythemic disorders with augmented HIF signaling.Blood. 2014 Jan 16;123(3):391-4. doi: 10.1182/blood-2013-10-534222. Epub 2013 Dec 2.
• [17] Novel homozygous VHL mutation in exon 2 is associated with congenital polycythemia but not with cancer.Blood. 2013 May 9;121(19):3918-24. doi: 10.1182/blood-2012-11-469296. Epub 2013 Mar 28.
• [18] Nfe2 is dispensable for early but required for adult thrombocyte formation and function in zebrafish.Blood Adv. 2018 Dec 11;2(23):3418-3427. doi: 10.1182/bloodadvances.2018021865.
• [19] Baicalein protects human vitiligo melanocytes from oxidative stress through activation of NF-E2-related factor2 (Nrf2) signaling pathway.Free Radic Biol Med. 2018 Dec;129:492-503. doi: 10.1016/j.freeradbiomed.2018.10.421. Epub 2018 Oct 18.
• [20] NFE2 Induces miR-423-5p to Promote Gluconeogenesis and Hyperglycemia by Repressing the Hepatic FAM3A-ATP-Akt Pathway.Diabetes. 2017 Jul;66(7):1819-1832. doi: 10.2337/db16-1172. Epub 2017 Apr 14.
• [21] The cytoprotective role of DJ-1 and p45 NFE2 against human primary alveolar type II cell injury and emphysema.Sci Rep. 2018 Feb 23;8(1):3555. doi: 10.1038/s41598-018-21790-3.
• [22] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [23] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [24] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [25] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [26] 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.
• [27] 3'-Azido-3'-deoxythymidine inhibits erythroid-specific transcription factors in human erythroid K562 leukemia cells. Eur J Haematol. 1996 Jan-Feb;56(1-2):62-7. doi: 10.1111/j.1600-0609.1996.tb00296.x.
• [28] Immunomodulatory derivative of thalidomide (IMiD CC-4047) induces a shift in lineage commitment by suppressing erythropoiesis and promoting myelopoiesis. Blood. 2005 May 15;105(10):3833-40. doi: 10.1182/blood-2004-03-0828. Epub 2004 Aug 3.
• [29] Oxidative stress involvement in chemically induced differentiation of K562 cells. Free Radic Biol Med. 2000 Jan 1;28(1):18-27.
• [30] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [31] 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.
• [32] Comprehensive transcriptome profiling of BET inhibitor-treated HepG2 cells. PLoS One. 2022 Apr 29;17(4):e0266966. doi: 10.1371/journal.pone.0266966. eCollection 2022.
• [33] Inter- and intra-laboratory study to determine the reproducibility of toxicogenomics datasets. Toxicology. 2011 Nov 28;290(1):50-8.
• [34] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [35] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [36] Phenolic metabolites of benzene inhibited the erythroid differentiation of K562 cells. Toxicol Lett. 2011 Jun 24;203(3):190-9. doi: 10.1016/j.toxlet.2011.03.012. Epub 2011 Mar 23.
• [37] Changes in DNA methylation of erythroid-specific genes in K562 cells exposed to catechol in long term. Toxicol In Vitro. 2017 Sep;43:21-28. doi: 10.1016/j.tiv.2017.05.019. Epub 2017 May 25.
• [38] Effects of chebulinic acid on differentiation of human leukemia K562 cells. Acta Pharmacol Sin. 2004 Feb;25(2):231-8.