Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKFK57F)

• DOT Name: Tetraspanin-4 (TSPAN4)
• Synonyms: Tspan-4; Novel antigen 2; NAG-2; Transmembrane 4 superfamily member 7
• Gene Name: TSPAN4
• Related Disease:
  Ependymoma
  Autism
  Esophageal squamous cell carcinoma
  Familial adenomatous polyposis
  Multiple sclerosis
  Neoplasm
• UniProt ID: TSN4_HUMAN
• Pfam ID: PF00335
• Sequence:
  MARACLQAVKYLMFAFNLLFWLGGCGVLGVGIWLAATQGSFATLSSSFPSLSAANLLIIT
  GAFVMAIGFVGCLGAIKENKCLLLTFFLLLLLVFLLEATIAILFFAYTDKIDRYAQQDLK
  KGLHLYGTQGNVGLTNAWSIIQTDFRCCGVSNYTDWFEVYNATRVPDSCCLEFSESCGLH
  APGTWWKAPCYETVKVWLQENLLAVGIFGLCTALVQILGLTFAMTMYCQVVKADTYCA
• Tissue Specificity: Expressed in multiple tissues but is absent in brain, lymphoid cells, and platelets.

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Ependymoma	DISUMRNZ	Definitive	Genetic Variation	[1]
Autism	DISV4V1Z	Strong	Biomarker	[2]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[3]
Familial adenomatous polyposis	DISW53RE	Strong	Biomarker	[4]
Multiple sclerosis	DISB2WZI	Strong	Biomarker	[5]
Neoplasm	DISZKGEW	Disputed	Biomarker	[6]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	Tetraspanin-4 (TSPAN4) affects the response to substance of Methotrexate.	[20]

3 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 Tetraspanin-4 (TSPAN4).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Tetraspanin-4 (TSPAN4).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Tetraspanin-4 (TSPAN4).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Tetraspanin-4 (TSPAN4).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Tetraspanin-4 (TSPAN4).	[9]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Tetraspanin-4 (TSPAN4).	[10]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Tetraspanin-4 (TSPAN4).	[11]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Tetraspanin-4 (TSPAN4).	[12]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Tetraspanin-4 (TSPAN4).	[13]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Tetraspanin-4 (TSPAN4).	[14]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Tetraspanin-4 (TSPAN4).	[15]
DTI-015	DMXZRW0	Approved	DTI-015 decreases the expression of Tetraspanin-4 (TSPAN4).	[16]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Tetraspanin-4 (TSPAN4).	[17]

References

• [1] Novel fusion genes and chimeric transcripts in ependymal tumors.Genes Chromosomes Cancer. 2016 Dec;55(12):944-953. doi: 10.1002/gcc.22392. Epub 2016 Jul 28.
• [2] VARPRISM: incorporating variant prioritization in tests of de novo mutation association.Genome Med. 2016 Aug 25;8(1):91. doi: 10.1186/s13073-016-0341-9.
• [3] Genome-scale CRISPR activation screening identifies a role of ELAVL2-CDKN1A axis in paclitaxel resistance in esophageal squamous cell carcinoma.Am J Cancer Res. 2019 Jun 1;9(6):1183-1200. eCollection 2019.
• [4] Epithelial Membrane Protein 2 and 1 integrin signaling regulate APC-mediated processes.Exp Cell Res. 2017 Jan 1;350(1):190-198. doi: 10.1016/j.yexcr.2016.11.021. Epub 2016 Nov 24.
• [5] Generational changes in multiple sclerosis phenotype in North African immigrants in France: A population-based observational study.PLoS One. 2018 Mar 27;13(3):e0194115. doi: 10.1371/journal.pone.0194115. eCollection 2018.
• [6] Positron emission tomography imaging of endometrial cancer using engineered anti-EMP2 antibody fragments.Mol Imaging Biol. 2013 Feb;15(1):68-78. doi: 10.1007/s11307-012-0558-y.
• [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] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [9] Retinoic acid receptor alpha amplifications and retinoic acid sensitivity in breast cancers. Clin Breast Cancer. 2013 Oct;13(5):401-8.
• [10] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [11] 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.
• [12] 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.
• [13] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [14] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [15] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [16] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [17] 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.
• [18] 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.
• [19] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [20] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.