Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTUAD95X)

• DOT Name: Transmembrane channel-like protein 8 (TMC8)
• Synonyms: Epidermodysplasia verruciformis protein 2
• Gene Name: TMC8
• Related Disease:
  Epidermodysplasia verruciformis, susceptibility to, 1
  Advanced cancer
  Cervical cancer
  Cervical carcinoma
  Cutaneous squamous cell carcinoma
  Epidermodysplasia verruciformis, susceptibility to, 2
  Human papillomavirus infection
  Neoplasm
  Skin cancer
  Systemic lupus erythematosus
  Actinic keratosis
  Epidermodysplasia verruciformis
  Head and neck cancer
  Head and neck carcinoma
  Squamous cell carcinoma
• UniProt ID: TMC8_HUMAN
• Pfam ID: PF07810
• Sequence:
  MLLPRSVSSERAPGVPEPEELWEAEMERLRGSGTPVRGLPYAMMDKRLIWQLREPAGVQT
  LRWQRWQRRRQTVERRLREAAQRLARGLGLWEGALYEIGGLFGTGIRSYFTFLRFLLLLN
  LLSLLLTASFVLLPLVWLRPPDPGPTLNLTLQCPGSRQSPPGVLRFHNQLWHVLTGRAFT
  NTYLFYGAYRVGPESSSVYSIRLAYLLSPLACLLLCFCGTLRRMVKGLPQKTLLGQGYQA
  PLSAKVFSSWDFCIRVQEAATIKKHEISNEFKVELEEGRRFQLMQQQTRAQTACRLLSYL
  RVNVLNGLLVVGAISAIFWATKYSQDNKEESLFLLLQYLPPGVIALVNFLGPLLFTFLVQ
  LENYPPNTEVNLTLIWCVVLKLASLGMFSVSLGQTILCIGRDKSSCESYGYNVCDYQCWE
  NSVGEELYKLSIFNFLLTVAFAFLVTLPRRLLVDRFSGRFWAWLEREEFLVPKNVLDIVA
  GQTVTWMGLFYCPLLPLLNSVFLFLTFYIKKYTLLKNSRASSRPFRASSSTFFFQLVLLL
  GLLLAAVPLGYVVSSIHSSWDCGLFTNYSAPWQVVPELVALGLPPIGQRALHYLGSHAFS
  FPLLIMLSLVLTVCVSQTQANARAIHRLRKQLVWQVQEKWHLVEDLSRLLPEPGPSDSPG
  PKYPASQASRPQSFCPGCPCPGSPGHQAPRPGPSVVDAAGLRSPCPGQHGAPASARRFRF
  PSGAEL
• Function: Probable ion channel.
• Tissue Specificity: Expressed in placenta, prostate and testis.

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Epidermodysplasia verruciformis, susceptibility to, 1	DISJZF5T	Definitive	Autosomal recessive	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Cervical cancer	DISFSHPF	Strong	Genetic Variation	[3]
Cervical carcinoma	DIST4S00	Strong	Genetic Variation	[3]
Cutaneous squamous cell carcinoma	DIS3LXUG	Strong	Genetic Variation	[4]
Epidermodysplasia verruciformis, susceptibility to, 2	DISOK5RA	Strong	Autosomal recessive	[5]
Human papillomavirus infection	DISX61LX	Strong	Genetic Variation	[6]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[3]
Skin cancer	DISTM18U	Strong	Biomarker	[7]
Systemic lupus erythematosus	DISI1SZ7	Strong	Altered Expression	[8]
Actinic keratosis	DISR1RC5	moderate	Genetic Variation	[9]
Epidermodysplasia verruciformis	DIS54WBS	Supportive	Autosomal recessive	[10]
Head and neck cancer	DISBPSQZ	Limited	Genetic Variation	[4]
Head and neck carcinoma	DISOU1DS	Limited	Genetic Variation	[4]
Squamous cell carcinoma	DISQVIFL	Limited	Genetic Variation	[9]

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 Transmembrane channel-like protein 8 (TMC8).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Transmembrane channel-like protein 8 (TMC8).	[18]

8 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 Transmembrane channel-like protein 8 (TMC8).	[12]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Transmembrane channel-like protein 8 (TMC8).	[13]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Transmembrane channel-like protein 8 (TMC8).	[14]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Transmembrane channel-like protein 8 (TMC8).	[15]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of Transmembrane channel-like protein 8 (TMC8).	[16]
Azathioprine	DMMZSXQ	Approved	Azathioprine increases the expression of Transmembrane channel-like protein 8 (TMC8).	[17]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Transmembrane channel-like protein 8 (TMC8).	[19]
2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE	DMNQL17	Investigative	2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE increases the expression of Transmembrane channel-like protein 8 (TMC8).	[20]

References

• [1] Genetics of epidermodysplasia verruciformis: Insights into host defense against papillomaviruses. Semin Immunol. 2006 Dec;18(6):362-74. doi: 10.1016/j.smim.2006.07.008. Epub 2006 Oct 2.
• [2] Common genetic variants and risk for HPV persistence and progression to cervical cancer.PLoS One. 2010 Jan 13;5(1):e8667. doi: 10.1371/journal.pone.0008667.
• [3] Variants of EVER1 and EVER2 (TMC6 and TMC8) and human papillomavirus status in patients with mucosal squamous cell carcinoma of the head and neck.Cancer Causes Control. 2016 Jun;27(6):809-15. doi: 10.1007/s10552-016-0749-y. Epub 2016 Apr 20.
• [4] A coding variant in TMC8 (EVER2) is associated with high risk HPV infection and head and neck cancer risk.PLoS One. 2015 Apr 8;10(4):e0123716. doi: 10.1371/journal.pone.0123716. eCollection 2015.
• [5] Epidermodysplasia Verruciformis: Genetic Heterogeneity and EVER1 and EVER2 Mutations Revealed by Genome-Wide Analysis. J Invest Dermatol. 2019 Jan;139(1):241-244. doi: 10.1016/j.jid.2018.07.010. Epub 2018 Jul 20.
• [6] Novel TMC8 splice site mutation in epidermodysplasia verruciformis and review of HPV infections in patients with the disease.J Eur Acad Dermatol Venereol. 2017 Oct;31(10):1722-1726. doi: 10.1111/jdv.14431. Epub 2017 Aug 4.
• [7] Loss of the HPV-infection resistance EVER2 protein impairs NF-B signaling pathways in keratinocytes.PLoS One. 2014 Feb 19;9(2):e89479. doi: 10.1371/journal.pone.0089479. eCollection 2014.
• [8] Gene profiling involved in immature CD4+ T lymphocyte responsible for systemic lupus erythematosus.Mol Immunol. 2006 Mar;43(9):1497-507. doi: 10.1016/j.molimm.2005.07.039. Epub 2005 Sep 6.
• [9] Possible association between actinic keratosis and the rs7208422 (c.917AT, p.N306l) polymorphism of the EVER2 gene in patients without epidermodysplasia verruciformis.Clin Exp Dermatol. 2015 Apr;40(3):318-23. doi: 10.1111/ced.12506. Epub 2014 Dec 12.
• [10] Mutations in two adjacent novel genes are associated with epidermodysplasia verruciformis. Nat Genet. 2002 Dec;32(4):579-81. doi: 10.1038/ng1044. Epub 2002 Nov 11.
• [11] 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.
• [12] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [13] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [14] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [15] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [16] Drinking-water arsenic exposure modulates gene expression in human lymphocytes from a U.S. population. Environ Health Perspect. 2008 Apr;116(4):524-31. doi: 10.1289/ehp.10861.
• [17] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [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] 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.
• [20] Preferential induction of the AhR gene battery in HepaRG cells after a single or repeated exposure to heterocyclic aromatic amines. Toxicol Appl Pharmacol. 2010 Nov 15;249(1):91-100.