Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKH50J4)

• DOT Name: Transmembrane channel-like protein 6 (TMC6)
• Synonyms: Epidermodysplasia verruciformis protein 1; Protein LAK-4
• Gene Name: TMC6
• Related Disease:
  Epidermodysplasia verruciformis, susceptibility to, 1
  Advanced cancer
  Cervical cancer
  Cervical carcinoma
  Cystic fibrosis
  Epidermodysplasia verruciformis
  Head-neck squamous cell carcinoma
  Human papillomavirus infection
  Skin cancer
  Squamous cell carcinoma
• UniProt ID: TMC6_HUMAN
• Pfam ID: PF07810
• Sequence:
  MAQPLAFILDVPETPGDQGQGPSPYDESEVHDSFQQLIQEQSQCTAQEGLELQQREREVT
  GSSQQTLWRPEGTQSTATLRILASMPSRTIGRSRGAIISQYYNRTVQLRCRSSRPLLGNF
  VRSAWPSLRLYDLELDPTALEEEEKQSLLVKELQSLAVAQRDHMLRGMPLSLAEKRSLRE
  KSRTPRGKWRGQPGSGGVCSCCGRLRYACVLALHSLGLALLSALQALMPWRYALKRIGGQ
  FGSSVLSYFLFLKTLLAFNALLLLLLVAFIMGPQVAFPPALPGPAPVCTGLELLTGAGCF
  THTVMYYGHYSNATLNQPCGSPLDGSQCTPRVGGLPYNMPLAYLSTVGVSFFITCITLVY
  SMAHSFGESYRVGSTSGIHAITVFCSWDYKVTQKRASRLQQDNIRTRLKELLAEWQLRHS
  PRSVCGRLRQAAVLGLVWLLCLGTALGCAVAVHVFSEFMIQSPEAAGQEAVLLVLPLVVG
  LLNLGAPYLCRVLAALEPHDSPVLEVYVAICRNLILKLAILGTLCYHWLGRRVGVLQGQC
  WEDFVGQELYRFLVMDFVLMLLDTLFGELVWRIISEKKLKRRRKPEFDIARNVLELIYGQ
  TLTWLGVLFSPLLPAVQIIKLLLVFYVKKTSLLANCQAPRRPWLASHMSTVFLTLLCFPA
  FLGAAVFLCYAVWQVKPSSTCGPFRTLDTMYEAGRVWVRHLEAAGPRVSWLPWVHRYLME
  NTFFVFLVSALLLAVIYLNIQVVRGQRKVICLLKEQISNEGEDKIFLINKLHSIYERKER
  EERSRVGTTEEAAAPPALLTDEQDA
• Function: Probable ion channel.
• Tissue Specificity: Expressed in placenta, prostate, testis, activated T-lymphocytes and lymphokine-activated killer (LAK) lymphocytes.
• Reactome Pathway: Neutrophil degranulation (R-HSA-6798695)

Molecular Interaction Atlas (MIA) of This DOT

10 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]
Cystic fibrosis	DIS2OK1Q	Strong	Genetic Variation	[4]
Epidermodysplasia verruciformis	DIS54WBS	Strong	Autosomal recessive	[5]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Biomarker	[6]
Human papillomavirus infection	DISX61LX	Strong	Genetic Variation	[6]
Skin cancer	DISTM18U	Strong	Biomarker	[7]
Squamous cell carcinoma	DISQVIFL	Limited	Genetic Variation	[8]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Etoposide	DMNH3PG	Approved	Transmembrane channel-like protein 6 (TMC6) affects the response to substance of Etoposide.	[29]
Topotecan	DMP6G8T	Approved	Transmembrane channel-like protein 6 (TMC6) affects the response to substance of Topotecan.	[29]

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 Transmembrane channel-like protein 6 (TMC6).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Transmembrane channel-like protein 6 (TMC6).	[23]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Transmembrane channel-like protein 6 (TMC6).	[25]

19 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 6 (TMC6).	[10]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Transmembrane channel-like protein 6 (TMC6).	[11]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Transmembrane channel-like protein 6 (TMC6).	[12]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Transmembrane channel-like protein 6 (TMC6).	[13]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Transmembrane channel-like protein 6 (TMC6).	[14]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Transmembrane channel-like protein 6 (TMC6).	[15]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Transmembrane channel-like protein 6 (TMC6).	[16]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Transmembrane channel-like protein 6 (TMC6).	[17]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Transmembrane channel-like protein 6 (TMC6).	[13]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Transmembrane channel-like protein 6 (TMC6).	[18]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of Transmembrane channel-like protein 6 (TMC6).	[19]
Azathioprine	DMMZSXQ	Approved	Azathioprine increases the expression of Transmembrane channel-like protein 6 (TMC6).	[20]
Propofol	DMB4OLE	Approved	Propofol increases the expression of Transmembrane channel-like protein 6 (TMC6).	[21]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Transmembrane channel-like protein 6 (TMC6).	[22]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene increases the expression of Transmembrane channel-like protein 6 (TMC6).	[11]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Transmembrane channel-like protein 6 (TMC6).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Transmembrane channel-like protein 6 (TMC6).	[26]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Transmembrane channel-like protein 6 (TMC6).	[27]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Transmembrane channel-like protein 6 (TMC6).	[28]

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] Genetic polymorphisms of FAS and EVER genes in a Greek population and their susceptibility to cervical cancer: a case control study.BMC Cancer. 2016 Nov 29;16(1):923. doi: 10.1186/s12885-016-2960-3.
• [4] Exome Sequencing of Phenotypic Extremes Identifies CAV2 and TMC6 as Interacting Modifiers of Chronic Pseudomonas aeruginosa Infection in Cystic Fibrosis.PLoS Genet. 2015 Jun 5;11(6):e1005273. doi: 10.1371/journal.pgen.1005273. eCollection 2015 Jun.
• [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] 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.
• [7] Characterization of the transmembrane channel-like (TMC) gene family: functional clues from hearing loss and epidermodysplasia verruciformis.Genomics. 2003 Sep;82(3):300-8. doi: 10.1016/s0888-7543(03)00154-x.
• [8] Cutaneous human papillomavirus infection, the EVER2 gene and incidence of squamous cell carcinoma: a case-control study.Int J Cancer. 2008 May 15;122(10):2377-9. doi: 10.1002/ijc.23377.
• [9] 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.
• [10] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [11] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [12] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [13] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [14] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [15] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [16] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [17] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [18] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [19] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [20] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [21] Propofol suppresses proliferation, migration, invasion, and tumor growth of liver cancer cells via suppressing cancer susceptibility candidate 9/phosphatase and tensin homolog/AKT serine/threonine kinase/mechanistic target of rapamycin kinase axis. Hum Exp Toxicol. 2022 Jan-Dec;41:9603271211065972. doi: 10.1177/09603271211065972.
• [22] 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.
• [23] 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.
• [24] 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.
• [25] 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.
• [26] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [27] 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.
• [28] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.
• [29] 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.