Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZDHT1D)

• DOT Name: Methylcytosine dioxygenase TET1 (TET1)
• Synonyms: EC 1.14.11.80; CXXC-type zinc finger protein 6; Leukemia-associated protein with a CXXC domain; Ten-eleven translocation 1 gene protein
• Gene Name: TET1
• Related Disease:
  Prostate cancer
  Prostate carcinoma
  Rett syndrome
  Adenocarcinoma
  Advanced cancer
  Alzheimer disease
  Autism spectrum disorder
  Bone osteosarcoma
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Cervical cancer
  Cervical carcinoma
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Depression
  Epithelial ovarian cancer
  Gastric cancer
  Glioma
  Hepatocellular carcinoma
  Liver cancer
  Neoplasm
  Neuralgia
  Non-small-cell lung cancer
  Osteosarcoma
  Ovarian cancer
  Ovarian neoplasm
  Psychotic disorder
  Renal cell carcinoma
  Squamous cell carcinoma
  Triple negative breast cancer
  Carcinoma
  Lung adenocarcinoma
  Lung cancer
  Lung carcinoma
  Metastatic malignant neoplasm
  Acute myelogenous leukaemia
  Adult glioblastoma
  Asthma
  Endometrial cancer
  Endometrial carcinoma
  Glioblastoma multiforme
  Rheumatoid arthritis
  Schizophrenia
  Seminoma
  Stomach cancer
• UniProt ID: TET1_HUMAN
• PDB ID: 6ASD
• EC Number: 1.14.11.80
• Pfam ID: PF12851 ; PF02008
• Sequence:
  MSRSRHARPSRLVRKEDVNKKKKNSQLRKTTKGANKNVASVKTLSPGKLKQLIQERDVKK
  KTEPKPPVPVRSLLTRAGAARMNLDRTEVLFQNPESLTCNGFTMALRSTSLSRRLSQPPL
  VVAKSKKVPLSKGLEKQHDCDYKILPALGVKHSENDSVPMQDTQVLPDIETLIGVQNPSL
  LKGKSQETTQFWSQRVEDSKINIPTHSGPAAEILPGPLEGTRCGEGLFSEETLNDTSGSP
  KMFAQDTVCAPFPQRATPKVTSQGNPSIQLEELGSRVESLKLSDSYLDPIKSEHDCYPTS
  SLNKVIPDLNLRNCLALGGSTSPTSVIKFLLAGSKQATLGAKPDHQEAFEATANQQEVSD
  TTSFLGQAFGAIPHQWELPGADPVHGEALGETPDLPEIPGAIPVQGEVFGTILDQQETLG
  MSGSVVPDLPVFLPVPPNPIATFNAPSKWPEPQSTVSYGLAVQGAIQILPLGSGHTPQSS
  SNSEKNSLPPVMAISNVENEKQVHISFLPANTQGFPLAPERGLFHASLGIAQLSQAGPSK
  SDRGSSQVSVTSTVHVVNTTVVTMPVPMVSTSSSSYTTLLPTLEKKKRKRCGVCEPCQQK
  TNCGECTYCKNRKNSHQICKKRKCEELKKKPSVVVPLEVIKENKRPQREKKPKVLKADFD
  NKPVNGPKSESMDYSRCGHGEEQKLELNPHTVENVTKNEDSMTGIEVEKWTQNKKSQLTD
  HVKGDFSANVPEAEKSKNSEVDKKRTKSPKLFVQTVRNGIKHVHCLPAETNVSFKKFNIE
  EFGKTLENNSYKFLKDTANHKNAMSSVATDMSCDHLKGRSNVLVFQQPGFNCSSIPHSSH
  SIINHHASIHNEGDQPKTPENIPSKEPKDGSPVQPSLLSLMKDRRLTLEQVVAIEALTQL
  SEAPSENSSPSKSEKDEESEQRTASLLNSCKAILYTVRKDLQDPNLQGEPPKLNHCPSLE
  KQSSCNTVVFNGQTTTLSNSHINSATNQASTKSHEYSKVTNSLSLFIPKSNSSKIDTNKS
  IAQGIITLDNCSNDLHQLPPRNNEVEYCNQLLDSSKKLDSDDLSCQDATHTQIEEDVATQ
  LTQLASIIKINYIKPEDKKVESTPTSLVTCNVQQKYNQEKGTIQQKPPSSVHNNHGSSLT
  KQKNPTQKKTKSTPSRDRRKKKPTVVSYQENDRQKWEKLSYMYGTICDIWIASKFQNFGQ
  FCPHDFPTVFGKISSSTKIWKPLAQTRSIMQPKTVFPPLTQIKLQRYPESAEEKVKVEPL
  DSLSLFHLKTESNGKAFTDKAYNSQVQLTVNANQKAHPLTQPSSPPNQCANVMAGDDQIR
  FQQVVKEQLMHQRLPTLPGISHETPLPESALTLRNVNVVCSGGITVVSTKSEEEVCSSSF
  GTSEFSTVDSAQKNFNDYAMNFFTNPTKNLVSITKDSELPTCSCLDRVIQKDKGPYYTHL
  GAGPSVAAVREIMENRYGQKGNAIRIEIVVYTGKEGKSSHGCPIAKWVLRRSSDEEKVLC
  LVRQRTGHHCPTAVMVVLIMVWDGIPLPMADRLYTELTENLKSYNGHPTDRRCTLNENRT
  CTCQGIDPETCGASFSFGCSWSMYFNGCKFGRSPSPRRFRIDPSSPLHEKNLEDNLQSLA
  TRLAPIYKQYAPVAYQNQVEYENVARECRLGSKEGRPFSGVTACLDFCAHPHRDIHNMNN
  GSTVVCTLTREDNRSLGVIPQDEQLHVLPLYKLSDTDEFGSKEGMEAKIKSGAIEVLAPR
  RKKRTCFTQPVPRSGKKRAAMMTEVLAHKIRAVEKKPIPRIKRKNNSTTTNNSKPSSLPT
  LGSNTETVQPEVKSETEPHFILKSSDNTKTYSLMPSAPHPVKEASPGFSWSPKTASATPA
  PLKNDATASCGFSERSSTPHCTMPSGRLSGANAAAADGPGISQLGEVAPLPTLSAPVMEP
  LINSEPSTGVTEPLTPHQPNHQPSFLTSPQDLASSPMEEDEQHSEADEPPSDEPLSDDPL
  SPAEEKLPHIDEYWSDSEHIFLDANIGGVAIAPAHGSVLIECARRELHATTPVEHPNRNH
  PTRLSLVFYQHKNLNKPQHGFELNKIKFEAKEAKNKKMKASEQKDQAANEGPEQSSEVNE
  LNQIPSHKALTLTHDNVVTVSPYALTHVAGPYNHWV
• Function: Dioxygenase that plays a key role in active DNA demethylation, by catalyzing the sequential oxidation of the modified genomic base 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC). In addition to its role in DNA demethylation, plays a more general role in chromatin regulation by recruiting histone modifying protein complexes to alter histone marks and chromatin accessibility, leading to both activation and repression of gene expression. Plays therefore a role in many biological processes, including stem cell maintenance, T- and B-cell development, inflammation regulation, genomic imprinting, neural activity or DNA repair. Involved in the balance between pluripotency and lineage commitment of cells and plays a role in embryonic stem cells maintenance and inner cell mass cell specification. Together with QSER1, plays an essential role in the protection and maintenance of transcriptional and developmental programs to inhibit the binding of DNMT3A/3B and therefore de novo methylation. May play a role in pancreatic beta-cell specification during development. In this context, may function as an upstream epigenetic regulator of PAX4 presumably through direct recruitment by FOXA2 to a PAX4 enhancer to preserve its unmethylated status, thereby potentiating PAX4 expression to adopt beta-cell fate during endocrine lineage commitment. Under DNA hypomethylation conditions, such as in female meiotic germ cells, may induce epigenetic reprogramming of pericentromeric heterochromatin (PCH), the constitutive heterochromatin of pericentromeric regions. PCH forms chromocenters in the interphase nucleus and chromocenters cluster at the prophase of meiosis. In this context, may also be essential for chromocenter clustering in a catalytic activity-independent manner, possibly through the recruitment polycomb repressive complex 1 (PRC1) to the chromocenters. During embryonic development, may be required for normal meiotic progression in oocytes and meiotic gene activation. Binds preferentially to DNA containing cytidine-phosphate-guanosine (CpG) dinucleotides over CpH (H=A, T, and C), hemimethylated-CpG and hemimethylated-hydroxymethyl-CpG ; [Isoform 1]: Dioxygenase that plays a key role in active DNA demethylation. Binds to promoters, particularly to those with high CG content. In hippocampal neurons, isoform 1 regulates the expression of a unique subset of genes compared to isoform 2, although some overlap exists between both isoforms, hence differentially regulates excitatory synaptic transmission. In hippocampal neuron cell cultures, isoform 1 controls both miniature excitatory postsynaptic current amplitude and frequency. Isoform 1 may regulate genes involved in hippocampal-dependent memory, leading to positive regulation of memory, contrary to isoform 2 that may decrease memory; [Isoform 2]: Dioxygenase that plays a key role in active DNA demethylation. As isoform 1, binds to promoters, particularly to those with high CG content, however displays reduced global chromatin affinity compared with isoform 1, leading to decreased global DNA demethylation compared with isoform 1. Contrary to isoform 1, isoform 2 localizes during S phase to sites of ongoing DNA replication in heterochromatin, causing a significant de novo 5hmC formation, globally, and more so in heterochromatin, including LINE 1 interspersed DNA repeats leading to their activation. In hippocampal neurons, isoform 2 regulates the expression of a unique subset of genes compared to isoform 1, although some overlap between both isoforms, hence differentially regulates excitatory synaptic transmission. In hippocampal neuron cell cultures, isoform 2 controls miniature excitatory postsynaptic current frequency, but not amplitude. Isoform 2 may regulate genes involved in hippocampal-dependent memory, leading to negative regulation of memory, contrary to isoform 1 that may improve memory. In immature and partially differentiated gonadotrope cells, directly represses luteinizing hormone gene LHB expression and does not catalyze 5hmC at the gene promoter.
• Tissue Specificity: Expressed in fetal heart, lung and brain, and in adult skeletal muscle, thymus and ovary. Not detected in adult heart, lung or brain. Up-regulated in glioblastoma cells (at protein level) .; [Isoform 1]: Expressed in embryonic stem cells (at protein level).
• Reactome Pathway: TET1,2,3 and TDG demethylate DNA (R-HSA-5221030)
• BioCyc Pathway: MetaCyc:ENSG00000138336-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

47 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Prostate cancer	DISF190Y	Definitive	Altered Expression	[1]
Prostate carcinoma	DISMJPLE	Definitive	Altered Expression	[1]
Rett syndrome	DISGG5UV	Definitive	Biomarker	[2]
Adenocarcinoma	DIS3IHTY	Strong	Altered Expression	[3]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[4]
Alzheimer disease	DISF8S70	Strong	Biomarker	[5]
Autism spectrum disorder	DISXK8NV	Strong	Biomarker	[6]
Bone osteosarcoma	DIST1004	Strong	Altered Expression	[7]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[8]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[8]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[9]
Cervical cancer	DISFSHPF	Strong	Biomarker	[10]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[10]
Colon cancer	DISVC52G	Strong	Biomarker	[4]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[4]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[11]
Depression	DIS3XJ69	Strong	Biomarker	[12]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[13]
Gastric cancer	DISXGOUK	Strong	Biomarker	[14]
Glioma	DIS5RPEH	Strong	Posttranslational Modification	[15]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[16]
Liver cancer	DISDE4BI	Strong	Altered Expression	[17]
Neoplasm	DISZKGEW	Strong	Altered Expression	[8]
Neuralgia	DISWO58J	Strong	Biomarker	[18]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Posttranslational Modification	[19]
Osteosarcoma	DISLQ7E2	Strong	Altered Expression	[7]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[20]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[20]
Psychotic disorder	DIS4UQOT	Strong	Altered Expression	[21]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[22]
Squamous cell carcinoma	DISQVIFL	Strong	Altered Expression	[3]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[8]
Carcinoma	DISH9F1N	moderate	Altered Expression	[23]
Lung adenocarcinoma	DISD51WR	moderate	Biomarker	[24]
Lung cancer	DISCM4YA	moderate	Biomarker	[25]
Lung carcinoma	DISTR26C	moderate	Biomarker	[25]
Metastatic malignant neoplasm	DIS86UK6	moderate	Posttranslational Modification	[26]
Acute myelogenous leukaemia	DISCSPTN	Disputed	Biomarker	[27]
Adult glioblastoma	DISVP4LU	Limited	Biomarker	[28]
Asthma	DISW9QNS	Limited	Biomarker	[29]
Endometrial cancer	DISW0LMR	Limited	Altered Expression	[30]
Endometrial carcinoma	DISXR5CY	Limited	Altered Expression	[30]
Glioblastoma multiforme	DISK8246	Limited	Biomarker	[28]
Rheumatoid arthritis	DISTSB4J	Limited	Biomarker	[31]
Schizophrenia	DISSRV2N	Limited	Altered Expression	[21]
Seminoma	DIS3J8LJ	Limited	Altered Expression	[32]
Stomach cancer	DISKIJSX	Limited	Biomarker	[14]

14 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 Methylcytosine dioxygenase TET1 (TET1).	[33]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Methylcytosine dioxygenase TET1 (TET1).	[34]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Methylcytosine dioxygenase TET1 (TET1).	[35]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Methylcytosine dioxygenase TET1 (TET1).	[36]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Methylcytosine dioxygenase TET1 (TET1).	[37]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Methylcytosine dioxygenase TET1 (TET1).	[38]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Methylcytosine dioxygenase TET1 (TET1).	[39]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Methylcytosine dioxygenase TET1 (TET1).	[40]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Methylcytosine dioxygenase TET1 (TET1).	[41]
Melphalan	DMOLNHF	Approved	Melphalan decreases the expression of Methylcytosine dioxygenase TET1 (TET1).	[42]
Ibuprofen	DM8VCBE	Approved	Ibuprofen increases the expression of Methylcytosine dioxygenase TET1 (TET1).	[35]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Methylcytosine dioxygenase TET1 (TET1).	[34]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Methylcytosine dioxygenase TET1 (TET1).	[43]
Resorcinol	DMM37C0	Investigative	Resorcinol increases the expression of Methylcytosine dioxygenase TET1 (TET1).	[41]

References

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• [6] Elevated 5-hydroxymethylcytosine in the Engrailed-2 (EN-2) promoter is associated with increased gene expression and decreased MeCP2 binding in autism cerebellum.Transl Psychiatry. 2014 Oct 7;4(10):e460. doi: 10.1038/tp.2014.87.
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• [9] Hypoxia Drives Breast Tumor Malignancy through a TET-TNF-p38-MAPK Signaling Axis.Cancer Res. 2015 Sep 15;75(18):3912-24. doi: 10.1158/0008-5472.CAN-14-3208. Epub 2015 Aug 20.
• [10] HOTAIR Knockdown Decreased the Activity Wnt/-Catenin Signaling Pathway and Increased the mRNA Levels of Its Negative Regulators in Hela Cells.Cell Physiol Biochem. 2019;53(6):948-960. doi: 10.33594/000000188.
• [11] Mono-ADP-ribosylation of H3R117 traps 5mC hydroxylase TET1 to impair demethylation of tumor suppressor gene TFPI2.Oncogene. 2019 May;38(18):3488-3503. doi: 10.1038/s41388-018-0671-8. Epub 2019 Jan 16.
• [12] High arrhythmic risk in antero-septal acute myocardial ischemia is explained by increased transmural reentry occurrence.Sci Rep. 2019 Nov 14;9(1):16803. doi: 10.1038/s41598-019-53221-2.
• [13] TET1 reprograms the epithelial ovarian cancer epigenome and reveals casein kinase 2 as a therapeutic target.J Pathol. 2019 Jul;248(3):363-376. doi: 10.1002/path.5266. Epub 2019 Apr 23.
• [14] CagA increases DNA methylation and decreases PTEN expression in human gastric cancer.Mol Med Rep. 2019 Jan;19(1):309-319. doi: 10.3892/mmr.2018.9654. Epub 2018 Nov 13.
• [15] Ten-eleven translocation 1 regulates methylation of autophagy-related genes in human glioma.Neuroreport. 2018 Jun 13;29(9):731-738. doi: 10.1097/WNR.0000000000001024.
• [16] Role of ten-eleven translocation proteins and 5-hydroxymethylcytosine in hepatocellular carcinoma.Cell Prolif. 2019 Jul;52(4):e12626. doi: 10.1111/cpr.12626. Epub 2019 Apr 29.
• [17] MiR-520b suppresses proliferation of hepatoma cells through targeting ten-eleven translocation 1 (TET1) mRNA.Biochem Biophys Res Commun. 2015 May 8;460(3):793-8. doi: 10.1016/j.bbrc.2015.03.108. Epub 2015 Mar 28.
• [18] TET1 Overexpression Mitigates Neuropathic Pain Through Rescuing the Expression of -Opioid Receptor and Kv1.2 in the Primary Sensory Neurons.Neurotherapeutics. 2019 Apr;16(2):491-504. doi: 10.1007/s13311-018-00689-x.
• [19] Clinical analysis of NSCLC patients reveals lack of association between EGFR mutation and TET1 downregulation.Cancer Gene Ther. 2017 Sep;24(9):373-380. doi: 10.1038/cgt.2017.26. Epub 2017 Aug 4.
• [20] TET1 promotes cisplatin-resistance via demethylating the vimentin promoter in ovarian cancer.Cell Biol Int. 2017 Apr;41(4):405-414. doi: 10.1002/cbin.10734. Epub 2017 Feb 16.
• [21] Tet1 overexpression leads to anxiety-like behavior and enhanced fear memories via the activation of calcium-dependent cascade through Egr1 expression in mice.FASEB J. 2018 Jan;32(1):390-403. doi: 10.1096/fj.201601340RR. Epub 2017 Sep 12.
• [22] Restored expression levels of TET1 decrease the proliferation and migration of renal carcinoma cells.Mol Med Rep. 2015 Oct;12(4):4837-42. doi: 10.3892/mmr.2015.4058. Epub 2015 Jul 8.
• [23] Cytosine 5-hydroxymethylation regulates VHL gene expression in renal clear cell carcinoma.Oncotarget. 2017 Jul 7;8(38):63780-63787. doi: 10.18632/oncotarget.19070. eCollection 2017 Sep 8.
• [24] Methyl-CpG Binding Domain Protein 2 Inhibits the Malignant Characteristic of Lung Adenocarcinoma through the Epigenetic Modulation of 10 to 11 Translocation 1 and miR-200s.Am J Pathol. 2019 May;189(5):1065-1076. doi: 10.1016/j.ajpath.2019.01.010. Epub 2019 Feb 5.
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• [29] TET1 contributes to allergic airway inflammation and regulates interferon and aryl hydrocarbon receptor signaling pathways in bronchial epithelial cells.Sci Rep. 2019 May 14;9(1):7361. doi: 10.1038/s41598-019-43767-6.
• [30] Metformin sensitizes endometrial cancer cells to progestin by targeting TET1 to downregulate glyoxalase I expression.Biomed Pharmacother. 2019 May;113:108712. doi: 10.1016/j.biopha.2019.108712. Epub 2019 Mar 6.
• [31] Evaluation of amplicor chlamydia PCR and LCX chlamydia LCR to detect Chlamydia trachomatis in synovial fluid.Clin Exp Rheumatol. 2002 Mar-Apr;20(2):185-92.
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• [34] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [35] Effects of Exposure to Acetaminophen and Ibuprofen on Fetal Germ Cell Development in Both Sexes in Rodent and Human Using Multiple Experimental Systems. Environ Health Perspect. 2018 Apr 16;126(4):047006. doi: 10.1289/EHP2307.
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