Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTMVM8R7)

• DOT Name: OTU domain-containing protein 7B (OTUD7B)
• Synonyms: EC 3.4.19.12; Cellular zinc finger anti-NF-kappa-B protein; Cezanne; Zinc finger A20 domain-containing protein 1; Zinc finger protein Cezanne
• Gene Name: OTUD7B
• Related Disease:
  Adenocarcinoma
  Breast carcinoma
  Hepatocellular carcinoma
  Lung adenocarcinoma
  Lung cancer
  Lung carcinoma
  Lung neoplasm
  Neoplasm
  Non-small-cell lung cancer
  Squamous cell carcinoma
  Pancreatic cancer
• UniProt ID: OTU7B_HUMAN
• PDB ID: 5LRU; 5LRV; 5LRW
• EC Number: 3.4.19.12
• Pfam ID: PF02338 ; PF14555 ; PF01754
• Sequence:
  MTLDMDAVLSDFVRSTGAEPGLARDLLEGKNWDVNAALSDFEQLRQVHAGNLPPSFSEGS
  GGSRTPEKGFSDREPTRPPRPILQRQDDIVQEKRLSRGISHASSSIVSLARSHVSSNGGG
  GGSNEHPLEMPICAFQLPDLTVYNEDFRSFIERDLIEQSMLVALEQAGRLNWWVSVDPTS
  QRLLPLATTGDGNCLLHAASLGMWGFHDRDLMLRKALYALMEKGVEKEALKRRWRWQQTQ
  QNKESGLVYTEDEWQKEWNELIKLASSEPRMHLGTNGANCGGVESSEEPVYESLEEFHVF
  VLAHVLRRPIVVVADTMLRDSGGEAFAPIPFGGIYLPLEVPASQCHRSPLVLAYDQAHFS
  ALVSMEQKENTKEQAVIPLTDSEYKLLPLHFAVDPGKGWEWGKDDSDNVRLASVILSLEV
  KLHLLHSYMNVKWIPLSSDAQAPLAQPESPTASAGDEPRSTPESGDSDKESVGSSSTSNE
  GGRRKEKSKRDREKDKKRADSVANKLGSFGKTLGSKLKKNMGGLMHSKGSKPGGVGTGLG
  GSSGTETLEKKKKNSLKSWKGGKEEAAGDGPVSEKPPAESVGNGGSKYSQEVMQSLSILR
  TAMQGEGKFIFVGTLKMGHRHQYQEEMIQRYLSDAEERFLAEQKQKEAERKIMNGGIGGG
  PPPAKKPEPDAREEQPTGPPAESRAMAFSTGYPGDFTIPRPSGGGVHCQEPRRQLAGGPC
  VGGLPPYATFPRQCPPGRPYPHQDSIPSLEPGSHSKDGLHRGALLPPPYRVADSYSNGYR
  EPPEPDGWAGGLRGLPPTQTKCKQPNCSFYGHPETNNFCSCCYREELRRREREPDGELLV
  HRF
• Function: Negative regulator of the non-canonical NF-kappa-B pathway that acts by mediating deubiquitination of TRAF3, an inhibitor of the NF-kappa-B pathway, thereby acting as a negative regulator of B-cell responses. In response to non-canonical NF-kappa-B stimuli, deubiquitinates 'Lys-48'-linked polyubiquitin chains of TRAF3, preventing TRAF3 proteolysis and over-activation of non-canonical NF-kappa-B. Negatively regulates mucosal immunity against infections. Deubiquitinates ZAP70, and thereby regulates T cell receptor (TCR) signaling that leads to the activation of NF-kappa-B. Plays a role in T cell homeostasis and is required for normal T cell responses, including production of IFNG and IL2. Mediates deubiquitination of EGFR. Has deubiquitinating activity toward 'Lys-11', 'Lys-48' and 'Lys-63'-linked polyubiquitin chains. Has a much higher catalytic rate with 'Lys-11'-linked polyubiquitin chains (in vitro); however the physiological significance of these data are unsure. Hydrolyzes both linear and branched forms of polyubiquitin.
• Tissue Specificity: Widely expressed. Abundant in kidney, heart and fetal liver. Expressed differentially among B-cells at distinct developmental stages. Higher expression seen in primary immature B-cells as compared to the mature cells.
• Reactome Pathway:
  Regulation of TNFR1 signaling (R-HSA-5357905)
  TNFR1-induced NF-kappa-B signaling pathway (R-HSA-5357956)
  Ovarian tumor domain proteases (R-HSA-5689896)
  TNFR1-induced proapoptotic signaling (R-HSA-5357786)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adenocarcinoma	DIS3IHTY	Strong	Altered Expression	[1]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[2]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[3]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[1]
Lung cancer	DISCM4YA	Strong	Altered Expression	[1]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[1]
Lung neoplasm	DISVARNB	Strong	Biomarker	[1]
Neoplasm	DISZKGEW	Strong	Altered Expression	[4]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[1]
Squamous cell carcinoma	DISQVIFL	Strong	Altered Expression	[1]
Pancreatic cancer	DISJC981	moderate	Biomarker	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of OTU domain-containing protein 7B (OTUD7B).	[6]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of OTU domain-containing protein 7B (OTUD7B).	[7]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of OTU domain-containing protein 7B (OTUD7B).	[8]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of OTU domain-containing protein 7B (OTUD7B).	[8]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of OTU domain-containing protein 7B (OTUD7B).	[9]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of OTU domain-containing protein 7B (OTUD7B).	[10]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of OTU domain-containing protein 7B (OTUD7B).	[11]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of OTU domain-containing protein 7B (OTUD7B).	[12]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the expression of OTU domain-containing protein 7B (OTUD7B).	[13]

2 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 OTU domain-containing protein 7B (OTUD7B).	[14]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of OTU domain-containing protein 7B (OTUD7B).	[15]

References

• [1] Upregulation of OTUD7B (Cezanne) Promotes Tumor Progression via AKT/VEGF Pathway in Lung Squamous Carcinoma and Adenocarcinoma.Front Oncol. 2019 Sep 11;9:862. doi: 10.3389/fonc.2019.00862. eCollection 2019.
• [2] Association analysis identifies 65 new breast cancer risk loci.Nature. 2017 Nov 2;551(7678):92-94. doi: 10.1038/nature24284. Epub 2017 Oct 23.
• [3] Cezanne predicts progression and adjuvant TACE response in hepatocellular carcinoma.Cell Death Dis. 2017 Sep 7;8(9):e3043. doi: 10.1038/cddis.2017.428.
• [4] Biological and clinical implications of retinoic acid-responsive genes in human hepatocellular carcinoma cells.J Hepatol. 2013 Nov;59(5):1037-44. doi: 10.1016/j.jhep.2013.06.024. Epub 2013 Jul 2.
• [5] Long noncoding RNA 00976 promotes pancreatic cancer progression through OTUD7B by sponging miR-137 involving EGFR/MAPK pathway.J Exp Clin Cancer Res. 2019 Nov 20;38(1):470. doi: 10.1186/s13046-019-1388-4.
• [6] 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.
• [7] 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.
• [8] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [9] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [10] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [11] 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.
• [12] 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.
• [13] Curcumin restores corticosteroid function in monocytes exposed to oxidants by maintaining HDAC2. Am J Respir Cell Mol Biol. 2008 Sep;39(3):312-23. doi: 10.1165/rcmb.2008-0012OC. Epub 2008 Apr 17.
• [14] 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.
• [15] 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.