Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTSUUV9N)

• DOT Name: Probable E3 ubiquitin-protein ligase DTX3 (DTX3)
• Synonyms: EC 2.3.2.27; Protein deltex-3; Deltex3; RING finger protein 154; RING-type E3 ubiquitin transferase DTX3
• Gene Name: DTX3
• Related Disease:
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Non-small-cell lung cancer
• UniProt ID: DTX3_HUMAN
• EC Number: 2.3.2.27
• Pfam ID: PF18102 ; PF13923
• Sequence:
  MSFVLSRMAACGGTCKNKVTVSKPVWDFLSKETPARLARLREEHRVSILIDGETSDIYVL
  QLSPQGPPPAPPNGLYLARKALKGLLKEAEKELKKAQRQGELMGCLALGGGGEHPEMHRA
  GPPPLRAAPLLPPGARGLPPPPPPLPPPLPPRLREEAEEQESTCPICLGEIQNAKTLEKC
  RHSFCEGCITRALQVKKACPMCGRFYGQLVGNQPQNGRMLVSKDATLLLPSYEKYGTIVI
  QYVFPPGVQGAEHPNPGVRYPGTTRVAYLPDCPEGNKVLTLFRKAFDQRLTFTIGTSMTT
  GRPNVITWNDIHHKTSCTGGPQLFGYPDPTYLTRVQEELRAKGITDD
• Function: Regulator of Notch signaling, a signaling pathway involved in cell-cell communications that regulates a broad spectrum of cell-fate determinations. Probably acts both as a positive and negative regulator of Notch, depending on the developmental and cell context. Functions as an ubiquitin ligase protein in vitro, suggesting that it may regulate the Notch pathway via some ubiquitin ligase activity.
• KEGG Pathway: Notch sig.ling pathway (hsa04330)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Strong	Biomarker	[1]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[1]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[1]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[2]

10 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 Probable E3 ubiquitin-protein ligase DTX3 (DTX3).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Probable E3 ubiquitin-protein ligase DTX3 (DTX3).	[4]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Probable E3 ubiquitin-protein ligase DTX3 (DTX3).	[5]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Probable E3 ubiquitin-protein ligase DTX3 (DTX3).	[6]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Probable E3 ubiquitin-protein ligase DTX3 (DTX3).	[7]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Probable E3 ubiquitin-protein ligase DTX3 (DTX3).	[8]
Enzalutamide	DMGL19D	Approved	Enzalutamide affects the expression of Probable E3 ubiquitin-protein ligase DTX3 (DTX3).	[9]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Probable E3 ubiquitin-protein ligase DTX3 (DTX3).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Probable E3 ubiquitin-protein ligase DTX3 (DTX3).	[12]
Glyphosate	DM0AFY7	Investigative	Glyphosate increases the expression of Probable E3 ubiquitin-protein ligase DTX3 (DTX3).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Probable E3 ubiquitin-protein ligase DTX3 (DTX3).	[10]

References

• [1] An integrated genomics approach identifies drivers of proliferation in luminal-subtype human breast cancer.Nat Genet. 2014 Oct;46(10):1051-9. doi: 10.1038/ng.3073. Epub 2014 Aug 24.
• [2] TOB1-AS1 suppresses non-small cell lung cancer cell migration and invasion through a ceRNA network.Exp Ther Med. 2019 Dec;18(6):4249-4258. doi: 10.3892/etm.2019.8103. Epub 2019 Oct 15.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] 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.
• [5] 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.
• [6] 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.
• [7] 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.
• [8] 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.
• [9] NOTCH signaling is activated in and contributes to resistance in enzalutamide-resistant prostate cancer cells. J Biol Chem. 2019 May 24;294(21):8543-8554. doi: 10.1074/jbc.RA118.006983. Epub 2019 Apr 2.
• [10] 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.
• [11] 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.
• [12] 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.
• [13] 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.