Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT76U3YF)

• DOT Name: Methylcytosine dioxygenase TET3 (TET3)
• Synonyms: EC 1.14.11.80
• Gene Name: TET3
• Related Disease:
  Beck-Fahrner syndrome
  Cerebral degeneration
  Stroke
  Adult glioblastoma
  Arteriosclerosis
  Atherosclerosis
  Autism spectrum disorder
  B-cell neoplasm
  Breast neoplasm
  Clear cell renal carcinoma
  Endometrial cancer
  Endometrial carcinoma
  Endometriosis
  Epithelial ovarian cancer
  Esophageal squamous cell carcinoma
  Glioblastoma multiforme
  Glioma
  Head and neck cancer
  Head and neck carcinoma
  Hepatocellular carcinoma
  Hidradenitis suppurativa
  Leiomyoma
  Malignant glioma
  Neoplasm
  Ovarian cancer
  Ovarian neoplasm
  Renal cell carcinoma
  Uterine fibroids
  Non-insulin dependent diabetes
  Peripheral arterial disease
  Vascular disease
  Acute myelogenous leukaemia
  Breast cancer
  Breast carcinoma
  Chronic myelomonocytic leukemia
  Myeloproliferative neoplasm
• UniProt ID: TET3_HUMAN
• PDB ID: 4Z3C
• EC Number: 1.14.11.80
• Pfam ID: PF12851 ; PF02008
• Sequence:
  MSQFQVPLAVQPDLPGLYDFPQRQVMVGSFPGSGLSMAGSESQLRGGGDGRKKRKRCGTC
  EPCRRLENCGACTSCTNRRTHQICKLRKCEVLKKKVGLLKEVEIKAGEGAGPWGQGAAVK
  TGSELSPVDGPVPGQMDSGPVYHGDSRQLSASGVPVNGAREPAGPSLLGTGGPWRVDQKP
  DWEAAPGPAHTARLEDAHDLVAFSAVAEAVSSYGALSTRLYETFNREMSREAGNNSRGPR
  PGPEGCSAGSEDLDTLQTALALARHGMKPPNCNCDGPECPDYLEWLEGKIKSVVMEGGEE
  RPRLPGPLPPGEAGLPAPSTRPLLSSEVPQISPQEGLPLSQSALSIAKEKNISLQTAIAI
  EALTQLSSALPQPSHSTPQASCPLPEALSPPAPFRSPQSYLRAPSWPVVPPEEHSSFAPD
  SSAFPPATPRTEFPEAWGTDTPPATPRSSWPMPRPSPDPMAELEQLLGSASDYIQSVFKR
  PEALPTKPKVKVEAPSSSPAPAPSPVLQREAPTPSSEPDTHQKAQTALQQHLHHKRSLFL
  EQVHDTSFPAPSEPSAPGWWPPPSSPVPRLPDRPPKEKKKKLPTPAGGPVGTEKAAPGIK
  PSVRKPIQIKKSRPREAQPLFPPVRQIVLEGLRSPASQEVQAHPPAPLPASQGSAVPLPP
  EPSLALFAPSPSRDSLLPPTQEMRSPSPMTALQPGSTGPLPPADDKLEELIRQFEAEFGD
  SFGLPGPPSVPIQDPENQQTCLPAPESPFATRSPKQIKIESSGAVTVLSTTCFHSEEGGQ
  EATPTKAENPLTPTLSGFLESPLKYLDTPTKSLLDTPAKRAQAEFPTCDCVEQIVEKDEG
  PYYTHLGSGPTVASIRELMEERYGEKGKAIRIEKVIYTGKEGKSSRGCPIAKWVIRRHTL
  EEKLLCLVRHRAGHHCQNAVIVILILAWEGIPRSLGDTLYQELTDTLRKYGNPTSRRCGL
  NDDRTCACQGKDPNTCGASFSFGCSWSMYFNGCKYARSKTPRKFRLAGDNPKEEEVLRKS
  FQDLATEVAPLYKRLAPQAYQNQVTNEEIAIDCRLGLKEGRPFAGVTACMDFCAHAHKDQ
  HNLYNGCTVVCTLTKEDNRCVGKIPEDEQLHVLPLYKMANTDEFGSEENQNAKVGSGAIQ
  VLTAFPREVRRLPEPAKSCRQRQLEARKAAAEKKKIQKEKLSTPEKIKQEALELAGITSD
  PGLSLKGGLSQQGLKPSLKVEPQNHFSSFKYSGNAVVESYSVLGNCRPSDPYSMNSVYSY
  HSYYAQPSLTSVNGFHSKYALPSFSYYGFPSSNPVFPSQFLGPGAWGHSGSSGSFEKKPD
  LHALHNSLSPAYGGAEFAELPSQAVPTDAHHPTPHHQQPAYPGPKEYLLPKAPLLHSVSR
  DPSPFAQSSNCYNRSIKQEPVDPLTQAEPVPRDAGKMGKTPLSEVSQNGGPSHLWGQYSG
  GPSMSPKRTNGVGGSWGVFSSGESPAIVPDKLSSFGASCLAPSHFTDGQWGLFPGEGQQA
  ASHSGGRLRGKPWSPCKFGNSTSALAGPSLTEKPWALGAGDFNSALKGSPGFQDKLWNPM
  KGEEGRIPAAGASQLDRAWQSFGLPLGSSEKLFGALKSEEKLWDPFSLEEGPAEEPPSKG
  AVKEEKGGGGAEEEEEELWSDSEHNFLDENIGGVAVAPAHGSILIECARRELHATTPLKK
  PNRCHPTRISLVFYQHKNLNQPNHGLALWEAKMKQLAERARARQEEAARLGLGQQEAKLY
  GKKRKWGGTVVAEPQQKEKKGVVPTRQALAVPTDSAVTVSSYAYTKVTGPYSRWI
• Function: Dioxygenase that catalyzes the conversion of the modified genomic base 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC) and plays a key role in epigenetic chromatin reprogramming in the zygote following fertilization. Also mediates subsequent conversion of 5hmC into 5-formylcytosine (5fC), and conversion of 5fC to 5-carboxylcytosine (5caC). Conversion of 5mC into 5hmC, 5fC and 5caC probably constitutes the first step in cytosine demethylation. Selectively binds to the promoter region of target genes and contributes to regulate the expression of numerous developmental genes. In zygotes, DNA demethylation occurs selectively in the paternal pronucleus before the first cell division, while the adjacent maternal pronucleus and certain paternally-imprinted loci are protected from this process. Participates in DNA demethylation in the paternal pronucleus by mediating conversion of 5mC into 5hmC, 5fC and 5caC. Does not mediate DNA demethylation of maternal pronucleus because of the presence of DPPA3/PGC7 on maternal chromatin that prevents TET3-binding to chromatin. In addition to its role in DNA demethylation, also involved in the recruitment of the O-GlcNAc transferase OGT to CpG-rich transcription start sites of active genes, thereby promoting histone H2B GlcNAcylation by OGT. Binds preferentially to DNA containing cytidine-phosphate-guanosine (CpG) dinucleotides over CpH (H=A, T, and C), hemimethylated-CpG and hemimethylated-hydroxymethyl-CpG.
• Tissue Specificity: Expressed in colon, muscle, adrenal gland and peripheral blood lymphocytes.
• Reactome Pathway:
  Chromatin modifications during the maternal to zygotic transition (MZT) (R-HSA-9821002)
  TET1,2,3 and TDG demethylate DNA (R-HSA-5221030)

Molecular Interaction Atlas (MIA) of This DOT

36 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Beck-Fahrner syndrome	DIS5QXQY	Definitive	Autosomal dominant	[1]
Cerebral degeneration	DISUMR0A	Definitive	Biomarker	[2]
Stroke	DISX6UHX	Definitive	Biomarker	[2]
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[3]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[4]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[4]
Autism spectrum disorder	DISXK8NV	Strong	Biomarker	[5]
B-cell neoplasm	DISVY326	Strong	Genetic Variation	[6]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[7]
Clear cell renal carcinoma	DISBXRFJ	Strong	Altered Expression	[8]
Endometrial cancer	DISW0LMR	Strong	Biomarker	[9]
Endometrial carcinoma	DISXR5CY	Strong	Biomarker	[9]
Endometriosis	DISX1AG8	Strong	Altered Expression	[10]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[11]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[12]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[3]
Glioma	DIS5RPEH	Strong	Biomarker	[13]
Head and neck cancer	DISBPSQZ	Strong	Posttranslational Modification	[14]
Head and neck carcinoma	DISOU1DS	Strong	Posttranslational Modification	[14]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[15]
Hidradenitis suppurativa	DIS3ZNAK	Strong	Altered Expression	[16]
Leiomyoma	DISLDDFN	Strong	Altered Expression	[17]
Malignant glioma	DISFXKOV	Strong	Altered Expression	[13]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[18]
Ovarian cancer	DISZJHAP	Strong	Altered Expression	[11]
Ovarian neoplasm	DISEAFTY	Strong	Altered Expression	[11]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[8]
Uterine fibroids	DISBZRMJ	Strong	Altered Expression	[17]
Non-insulin dependent diabetes	DISK1O5Z	moderate	Altered Expression	[19]
Peripheral arterial disease	DIS78WFB	moderate	Altered Expression	[19]
Vascular disease	DISVS67S	moderate	Biomarker	[19]
Acute myelogenous leukaemia	DISCSPTN	Limited	Biomarker	[20]
Breast cancer	DIS7DPX1	Limited	Altered Expression	[21]
Breast carcinoma	DIS2UE88	Limited	Altered Expression	[21]
Chronic myelomonocytic leukemia	DISIL8UR	Limited	Biomarker	[20]
Myeloproliferative neoplasm	DIS5KAPA	Limited	Posttranslational Modification	[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 Methylcytosine dioxygenase TET3 (TET3).	[22]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Methylcytosine dioxygenase TET3 (TET3).	[28]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Methylcytosine dioxygenase TET3 (TET3).	[30]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Methylcytosine dioxygenase TET3 (TET3).	[23]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Methylcytosine dioxygenase TET3 (TET3).	[24]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Methylcytosine dioxygenase TET3 (TET3).	[25]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Methylcytosine dioxygenase TET3 (TET3).	[26]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Methylcytosine dioxygenase TET3 (TET3).	[27]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Methylcytosine dioxygenase TET3 (TET3).	[29]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Methylcytosine dioxygenase TET3 (TET3).	[31]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Methylcytosine dioxygenase TET3 (TET3).	[32]

References

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• [2] Induction of DNA Hydroxymethylation Protects the Brain After Stroke.Stroke. 2019 Sep;50(9):2513-2521. doi: 10.1161/STROKEAHA.119.025665. Epub 2019 Jul 22.
• [3] Epigenetic downregulation of TET3 reduces genome-wide 5hmC levels and promotes glioblastoma tumorigenesis.Int J Cancer. 2020 Jan 15;146(2):373-387. doi: 10.1002/ijc.32520. Epub 2019 Jul 1.
• [4] Tet3 enhances IL-6 expression through up-regulation of 5-hmC in IL-6 promoter in chronic hypoxia induced atherosclerosis in offspring rats.Life Sci. 2019 Sep 1;232:116601. doi: 10.1016/j.lfs.2019.116601. Epub 2019 Jun 25.
• [5] 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.
• [6] TET enzymes control antibody production and shape the mutational landscape in germinal centre B cells.FEBS J. 2019 Sep;286(18):3566-3581. doi: 10.1111/febs.14934. Epub 2019 Jun 3.
• [7] 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.
• [8] TOP2A, HELLS, ATAD2, and TET3 Are Novel Prognostic Markers in Renal Cell Carcinoma.Urology. 2017 Apr;102:265.e1-265.e7. doi: 10.1016/j.urology.2016.12.050. Epub 2017 Jan 6.
• [9] Differential expression of ten-eleven translocation genes in endometrial cancers.Tumour Biol. 2017 Mar;39(3):1010428317695017. doi: 10.1177/1010428317695017.
• [10] Ten-Eleven Translocation Genes are Downregulated in Endometriosis.Curr Mol Med. 2016;16(3):288-98. doi: 10.2174/1566524016666160225153844.
• [11] TET3 inhibits TGF-1-induced epithelial-mesenchymal transition by demethylating miR-30d precursor gene in ovarian cancer cells.J Exp Clin Cancer Res. 2016 May 4;35:72. doi: 10.1186/s13046-016-0350-y.
• [12] Loss of 5-Hydroxymethylcytosine Is an Independent Unfavorable Prognostic Factor for Esophageal Squamous Cell Carcinoma.PLoS One. 2016 Apr 6;11(4):e0153100. doi: 10.1371/journal.pone.0153100. eCollection 2016.
• [13] Integrin 6 signaling induces STAT3-TET3-mediated hydroxymethylation of genes critical for maintenance of glioma stem cells.Oncogene. 2020 Mar;39(10):2156-2169. doi: 10.1038/s41388-019-1134-6. Epub 2019 Dec 9.
• [14] Association of TET3 epigenetic inactivation with head and neck cancer.Oncotarget. 2018 May 11;9(36):24480-24493. doi: 10.18632/oncotarget.25333. eCollection 2018 May 11.
• [15] Decrease of 5-hydroxymethylcytosine is associated with progression of hepatocellular carcinoma through downregulation of TET1.PLoS One. 2013 May 9;8(5):e62828. doi: 10.1371/journal.pone.0062828. Print 2013.
• [16] Reduced ten-eleven translocation and isocitrate dehydrogenase expression in inflammatory hidradenitis suppurativa lesions.Eur J Dermatol. 2018 Aug 1;28(4):449-456. doi: 10.1684/ejd.2018.3369.
• [17] 5-Hydroxymethylcytosine promotes proliferation of human uterine leiomyoma: a biological link to a new epigenetic modification in benign tumors.J Clin Endocrinol Metab. 2014 Nov;99(11):E2437-45. doi: 10.1210/jc.2014-2264. Epub 2014 Jul 24.
• [18] Impact of polymorphisms within genes involved in regulating DNA methylation in patients with metastatic colorectal cancer enrolled in three independent, randomised, open-label clinical trials: a meta-analysis from TRIBE, MAVERICC and FIRE-3.Eur J Cancer. 2019 Apr;111:138-147. doi: 10.1016/j.ejca.2019.01.105. Epub 2019 Mar 7.
• [19] Reduced mRNA and Protein Expression Levels of Tet Methylcytosine Dioxygenase 3 in Endothelial Progenitor Cells of Patients of Type 2 Diabetes With Peripheral Artery Disease.Front Immunol. 2018 Dec 6;9:2859. doi: 10.3389/fimmu.2018.02859. eCollection 2018.
• [20] Genetic characterization of TET1, TET2, and TET3 alterations in myeloid malignancies.Blood. 2009 Jul 2;114(1):144-7. doi: 10.1182/blood-2009-03-210039. Epub 2009 May 6.
• [21] Reduced Expression of TET1, TET2, TET3 and TDG mRNAs Are Associated with Poor Prognosis of Patients with Early Breast Cancer.PLoS One. 2015 Jul 24;10(7):e0133896. doi: 10.1371/journal.pone.0133896. eCollection 2015.
• [22] 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.
• [23] Oxidative stress-induced TET1 upregulation mediates active DNA demethylation in human gastric epithelial cells. J Toxicol Sci. 2023;48(5):273-283. doi: 10.2131/jts.48.273.
• [24] 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.
• [25] 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.
• [26] Synergistic activity of BET protein antagonist-based combinations in mantle cell lymphoma cells sensitive or resistant to ibrutinib. Blood. 2015 Sep 24;126(13):1565-74.
• [27] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [28] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [29] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [30] 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.
• [31] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [32] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.