Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1MGXT0)

• DOT Name: Nuclear factor erythroid 2-related factor 3 (NFE2L3)
• Synonyms: NF-E2-related factor 3; NFE2-related factor 3; Nuclear factor, erythroid derived 2, like 3
• Gene Name: NFE2L3
• Related Disease:
  Adult lymphoma
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Colorectal carcinoma
  Haematological malignancy
  Hepatocellular carcinoma
  Lymphoblastic lymphoma
  Lymphoma
  Pediatric lymphoma
  Clear cell renal carcinoma
  Colon adenocarcinoma
  Colon cancer
  Colon carcinoma
  Neoplasm
• UniProt ID: NF2L3_HUMAN
• Pfam ID: PF03131
• Sequence:
  MKHLKRWWSAGGGLLHLTLLLSLAGLRVDLDLYLLLPPPTLLQDELLFLGGPASSAYALS
  PFSASGGWGRAGHLHPKGRELDPAAPPEGQLLREVRALGVPFVPRTSVDAWLVHSVAAGS
  ADEAHGLLGAAAASSTGGAGASVDGGSQAVQGGGGDPRAARSGPLDAGEEEKAPAEPTAQ
  VPDAGGCASEENGVLREKHEAVDHSSQHEENEERVSAQKENSLQQNDDDENKIAEKPDWE
  AEKTTESRNERHLNGTDTSFSLEDLFQLLSSQPENSLEGISLGDIPLPGSISDGMNSSAH
  YHVNFSQAISQDVNLHEAILLCPNNTFRRDPTARTSQSQEPFLQLNSHTTNPEQTLPGTN
  LTGFLSPVDNHMRNLTSQDLLYDLDINIFDEINLMSLATEDNFDPIDVSQLFDEPDSDSG
  LSLDSSHNNTSVIKSNSSHSVCDEGAIGYCTDHESSSHHDLEGAVGGYYPEPSKLCHLDQ
  SDSDFHGDLTFQHVFHNHTYHLQPTAPESTSEPFPWPGKSQKIRSRYLEDTDRNLSRDEQ
  RAKALHIPFSVDEIVGMPVDSFNSMLSRYYLTDLQVSLIRDIRRRGKNKVAAQNCRKRKL
  DIILNLEDDVCNLQAKKETLKREQAQCNKAINIMKQKLHDLYHDIFSRLRDDQGRPVNPN
  HYALQCTHDGSILIVPKELVASGHKKETQKGKRK
• Function: Activates erythroid-specific, globin gene expression.
• Tissue Specificity: Highly expressed in human placenta and also in B-cell and monocyte cell lines. Low expression in heart, brain, lung, skeletal muscle, kidney and pancreas.

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult lymphoma	DISK8IZR	Strong	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[3]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[3]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[2]
Haematological malignancy	DISCDP7W	Strong	Altered Expression	[1]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[4]
Lymphoblastic lymphoma	DISB9ZYC	Strong	Biomarker	[1]
Lymphoma	DISN6V4S	Strong	Biomarker	[1]
Pediatric lymphoma	DIS51BK2	Strong	Biomarker	[1]
Clear cell renal carcinoma	DISBXRFJ	Limited	Posttranslational Modification	[5]
Colon adenocarcinoma	DISDRE0J	Limited	Altered Expression	[6]
Colon cancer	DISVC52G	Limited	Biomarker	[6]
Colon carcinoma	DISJYKUO	Limited	Biomarker	[6]
Neoplasm	DISZKGEW	Limited	Biomarker	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Nuclear factor erythroid 2-related factor 3 (NFE2L3).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Nuclear factor erythroid 2-related factor 3 (NFE2L3).	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Nuclear factor erythroid 2-related factor 3 (NFE2L3).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Nuclear factor erythroid 2-related factor 3 (NFE2L3).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Nuclear factor erythroid 2-related factor 3 (NFE2L3).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Nuclear factor erythroid 2-related factor 3 (NFE2L3).	[11]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Nuclear factor erythroid 2-related factor 3 (NFE2L3).	[12]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Nuclear factor erythroid 2-related factor 3 (NFE2L3).	[13]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Nuclear factor erythroid 2-related factor 3 (NFE2L3).	[14]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Nuclear factor erythroid 2-related factor 3 (NFE2L3).	[15]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Nuclear factor erythroid 2-related factor 3 (NFE2L3).	[16]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Nuclear factor erythroid 2-related factor 3 (NFE2L3).	[17]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Nuclear factor erythroid 2-related factor 3 (NFE2L3).	[15]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of Nuclear factor erythroid 2-related factor 3 (NFE2L3).	[18]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Nuclear factor erythroid 2-related factor 3 (NFE2L3).	[19]
Indomethacin	DMSC4A7	Approved	Indomethacin increases the expression of Nuclear factor erythroid 2-related factor 3 (NFE2L3).	[18]
Cyclophosphamide	DM4O2Z7	Approved	Cyclophosphamide decreases the expression of Nuclear factor erythroid 2-related factor 3 (NFE2L3).	[20]
Lindane	DMB8CNL	Approved	Lindane decreases the expression of Nuclear factor erythroid 2-related factor 3 (NFE2L3).	[20]
Vitamin C	DMXJ7O8	Approved	Vitamin C decreases the expression of Nuclear factor erythroid 2-related factor 3 (NFE2L3).	[12]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Nuclear factor erythroid 2-related factor 3 (NFE2L3).	[21]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Nuclear factor erythroid 2-related factor 3 (NFE2L3).	[16]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Nuclear factor erythroid 2-related factor 3 (NFE2L3).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Nuclear factor erythroid 2-related factor 3 (NFE2L3).	[23]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Nuclear factor erythroid 2-related factor 3 (NFE2L3).	[24]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Nuclear factor erythroid 2-related factor 3 (NFE2L3).	[25]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Nuclear factor erythroid 2-related factor 3 (NFE2L3).	[20]

References

• [1] Nfe2l3 (Nrf3) deficiency predisposes mice to T-cell lymphoblastic lymphoma.Blood. 2011 Feb 10;117(6):2005-8. doi: 10.1182/blood-2010-02-271460. Epub 2010 Dec 8.
• [2] New addiction to the NRF2-related factor NRF3 in cancer cells: Ubiquitin-independent proteolysis through the 20S proteasome.Cancer Sci. 2020 Jan;111(1):6-14. doi: 10.1111/cas.14244. Epub 2019 Dec 14.
• [3] NRF3 suppresses breast cancer cell metastasis and cell proliferation and is a favorable predictor of survival in breast cancer.Onco Targets Ther. 2019 Apr 18;12:3019-3030. doi: 10.2147/OTT.S197409. eCollection 2019.
• [4] Short hairpin RNA-mediated knockdown of nuclear factor erythroid 2-like 3 exhibits tumor-suppressing effects in hepatocellular carcinoma cells.World J Gastroenterol. 2019 Mar 14;25(10):1210-1223. doi: 10.3748/wjg.v25.i10.1210.
• [5] LAT, HOXD3 and NFE2L3 identified as novel DNA methylation-driven genes and prognostic markers in human clear cell renal cell carcinoma by integrative bioinformatics approaches.J Cancer. 2019 Oct 22;10(26):6726-6737. doi: 10.7150/jca.35641. eCollection 2019.
• [6] NFE2L3 Controls Colon Cancer Cell Growth through Regulation of DUX4, a CDK1 Inhibitor.Cell Rep. 2019 Nov 5;29(6):1469-1481.e9. doi: 10.1016/j.celrep.2019.09.087.
• [7] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [8] 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.
• [9] 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.
• [10] 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.
• [11] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [12] Natural antioxidants exhibit chemopreventive characteristics through the regulation of CNC b-Zip transcription factors in estrogen-induced breast carcinogenesis. J Biochem Mol Toxicol. 2014 Dec;28(12):529-38.
• [13] 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.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] 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.
• [18] Evaluation of developmental toxicity using undifferentiated human embryonic stem cells. J Appl Toxicol. 2015 Feb;35(2):205-18.
• [19] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [20] Transcriptome-based functional classifiers for direct immunotoxicity. Arch Toxicol. 2014 Mar;88(3):673-89.
• [21] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [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] 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.
• [24] 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.
• [25] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.