Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTR9PH95)

• DOT Name: Transducin-like enhancer protein 3 (TLE3)
• Synonyms: Enhancer of split groucho-like protein 3; ESG3
• Gene Name: TLE3
• Related Disease:
  Advanced cancer
  Alzheimer disease
  Amyotrophic lateral sclerosis type 1
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Epithelial ovarian cancer
  Familial amyotrophic lateral sclerosis
  Melanoma
  Neoplasm
  Ovarian cancer
  Ovarian neoplasm
  Prostate cancer
  Prostate carcinoma
  Prostate neoplasm
  Meningioma
  Triple negative breast cancer
  Type-1/2 diabetes
  Adult lymphoma
  Lymphoma
  Non-insulin dependent diabetes
  Obesity
  Pediatric lymphoma
  Rheumatoid arthritis
• UniProt ID: TLE3_HUMAN
• Pfam ID: PF03920 ; PF00400
• Sequence:
  MYPQGRHPAPHQPGQPGFKFTVAESCDRIKDEFQFLQAQYHSLKVEYDKLANEKTEMQRH
  YVMYYEMSYGLNIEMHKQTEIAKRLNTILAQIMPFLSQEHQQQVAQAVERAKQVTMTELN
  AIIGQQQLQAQHLSHATHGPPVQLPPHPSGLQPPGIPPVTGSSSGLLALGALGSQAHLTV
  KDEKNHHELDHRERESSANNSVSPSESLRASEKHRGSADYSMEAKKRKAEEKDSLSRYDS
  DGDKSDDLVVDVSNEDPATPRVSPAHSPPENGLDKARSLKKDAPTSPASVASSSSTPSSK
  TKDLGHNDKSSTPGLKSNTPTPRNDAPTPGTSTTPGLRSMPGKPPGMDPIGIMASALRTP
  ISITSSYAAPFAMMSHHEMNGSLTSPGAYAGLHNIPPQMSAAAAAAAAAYGRSPMVSFGA
  VGFDPHPPMRATGLPSSLASIPGGKPAYSFHVSADGQMQPVPFPHDALAGPGIPRHARQI
  NTLSHGEVVCAVTISNPTRHVYTGGKGCVKIWDISQPGSKSPISQLDCLNRDNYIRSCKL
  LPDGRTLIVGGEASTLTIWDLASPTPRIKAELTSSAPACYALAISPDAKVCFSCCSDGNI
  AVWDLHNQTLVRQFQGHTDGASCIDISHDGTKLWTGGLDNTVRSWDLREGRQLQQHDFTS
  QIFSLGYCPTGEWLAVGMESSNVEVLHHTKPDKYQLHLHESCVLSLKFAYCGKWFVSTGK
  DNLLNAWRTPYGASIFQSKESSSVLSCDISADDKYIVTGSGDKKATVYEVIY
• Function: Transcriptional corepressor that binds to a number of transcription factors. Inhibits the transcriptional activation mediated by CTNNB1 and TCF family members in Wnt signaling. The effects of full-length TLE family members may be modulated by association with dominant-negative AES.
• Tissue Specificity: Placenta and lung.
• KEGG Pathway:
  Wnt sig.ling pathway (hsa04310)
  Notch sig.ling pathway (hsa04330)
• Reactome Pathway:
  Deactivation of the beta-catenin transactivating complex (R-HSA-3769402)
  Repression of WNT target genes (R-HSA-4641265)
  Estrogen-dependent gene expression (R-HSA-9018519)
  Formation of the beta-catenin (R-HSA-201722)

Molecular Interaction Atlas (MIA) of This DOT

24 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Alzheimer disease	DISF8S70	Strong	Biomarker	[2]
Amyotrophic lateral sclerosis type 1	DIS5A2M0	Strong	Biomarker	[3]
Breast cancer	DIS7DPX1	Strong	Biomarker	[4]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[4]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[4]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[5]
Familial amyotrophic lateral sclerosis	DISWZ9CJ	Strong	Biomarker	[3]
Melanoma	DIS1RRCY	Strong	Altered Expression	[6]
Neoplasm	DISZKGEW	Strong	Altered Expression	[5]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[5]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[5]
Prostate cancer	DISF190Y	Strong	Biomarker	[7]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[7]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[7]
Meningioma	DISPT4TG	moderate	Biomarker	[8]
Triple negative breast cancer	DISAMG6N	moderate	Altered Expression	[9]
Type-1/2 diabetes	DISIUHAP	moderate	Biomarker	[10]
Adult lymphoma	DISK8IZR	Limited	Altered Expression	[11]
Lymphoma	DISN6V4S	Limited	Altered Expression	[11]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Biomarker	[12]
Obesity	DIS47Y1K	Limited	Biomarker	[10]
Pediatric lymphoma	DIS51BK2	Limited	Altered Expression	[11]
Rheumatoid arthritis	DISTSB4J	Limited	Biomarker	[13]

5 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 Transducin-like enhancer protein 3 (TLE3).	[14]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Transducin-like enhancer protein 3 (TLE3).	[21]
Quercetin	DM3NC4M	Approved	Quercetin increases the phosphorylation of Transducin-like enhancer protein 3 (TLE3).	[22]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Transducin-like enhancer protein 3 (TLE3).	[22]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Transducin-like enhancer protein 3 (TLE3).	[22]

13 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 Transducin-like enhancer protein 3 (TLE3).	[15]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Transducin-like enhancer protein 3 (TLE3).	[16]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Transducin-like enhancer protein 3 (TLE3).	[17]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Transducin-like enhancer protein 3 (TLE3).	[18]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Transducin-like enhancer protein 3 (TLE3).	[19]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Transducin-like enhancer protein 3 (TLE3).	[20]
DTI-015	DMXZRW0	Approved	DTI-015 decreases the expression of Transducin-like enhancer protein 3 (TLE3).	[23]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Transducin-like enhancer protein 3 (TLE3).	[24]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Transducin-like enhancer protein 3 (TLE3).	[25]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Transducin-like enhancer protein 3 (TLE3).	[26]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Transducin-like enhancer protein 3 (TLE3).	[27]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Transducin-like enhancer protein 3 (TLE3).	[28]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride increases the expression of Transducin-like enhancer protein 3 (TLE3).	[29]

References

• [1] RNF6 Promotes Colorectal Cancer by Activating the Wnt/-Catenin Pathway via Ubiquitination of TLE3.Cancer Res. 2018 Apr 15;78(8):1958-1971. doi: 10.1158/0008-5472.CAN-17-2683. Epub 2018 Jan 26.
• [2] Ginsenoside Rg3 Prevents Cognitive Impairment by Improving Mitochondrial Dysfunction in the Rat Model of Alzheimer's Disease.J Agric Food Chem. 2019 Sep 11;67(36):10048-10058. doi: 10.1021/acs.jafc.9b03793. Epub 2019 Aug 27.
• [3] Differential expression of inflammation- and apoptosis-related genes in spinal cords of a mutant SOD1 transgenic mouse model of familial amyotrophic lateral sclerosis.J Neurochem. 2002 Jan;80(1):158-67. doi: 10.1046/j.0022-3042.2001.00683.x.
• [4] Relevance of breast cancer antiestrogen resistance genes in human breast cancer progression and tamoxifen resistance.J Clin Oncol. 2009 Feb 1;27(4):542-9. doi: 10.1200/JCO.2008.17.1462. Epub 2008 Dec 15.
• [5] Transducin-Like Enhancer of Split 3 (TLE3) Expression Is Associated with Taxane Sensitivity in Nonserous Ovarian Carcinoma in a Three-Cohort Study.Cancer Epidemiol Biomarkers Prev. 2018 Jun;27(6):680-688. doi: 10.1158/1055-9965.EPI-17-1101. Epub 2018 Mar 12.
• [6] Transducin-like enhancer of split 3 regulates proliferation of melanoma cells via histone deacetylase activity.Oncotarget. 2019 Jan 8;10(3):404-414. doi: 10.18632/oncotarget.26552. eCollection 2019 Jan 8.
• [7] Splice variants of TLE family genes and up-regulation of a TLE3 isoform in prostate tumors.Biochem Biophys Res Commun. 2007 Dec 28;364(4):918-23. doi: 10.1016/j.bbrc.2007.10.097. Epub 2007 Oct 26.
• [8] Meningioma transcript profiles reveal deregulated Notch signaling pathway.Cancer Res. 2005 Jun 15;65(12):5070-5. doi: 10.1158/0008-5472.CAN-05-0240.
• [9] Quadruple Negative Breast Cancers (QNBC) Demonstrate Subtype Consistency among Primary and Recurrent or Metastatic Breast Cancer.Transl Oncol. 2019 Mar;12(3):493-501. doi: 10.1016/j.tranon.2018.11.008. Epub 2018 Dec 27.
• [10] Loss of TLE3 promotes the mitochondrial program in beige adipocytes and improves glucose metabolism.Genes Dev. 2019 Jul 1;33(13-14):747-762. doi: 10.1101/gad.321059.118. Epub 2019 May 23.
• [11] The effects of a growth-inhibiting tripeptide, acetylGlu-Ser-GlyNH2 (Ac-ESG), on gene expression and cell cycle progression of two lymphoma cell lines.Anticancer Res. 2003 Jul-Aug;23(4):3159-65.
• [12] Transducin-like enhancer of split 3 (TLE3) in adipose tissue is increased in situations characterized by decreased PPAR gene expression.J Mol Med (Berl). 2015 Jan;93(1):83-92. doi: 10.1007/s00109-014-1207-5. Epub 2014 Sep 25.
• [13] High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis.Nat Genet. 2012 Dec;44(12):1336-40. doi: 10.1038/ng.2462. Epub 2012 Nov 11.
• [14] 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.
• [15] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [16] 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.
• [17] 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.
• [18] 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.
• [19] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [20] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [21] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [22] 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.
• [23] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [24] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [25] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [26] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [27] 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.
• [28] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.
• [29] The contact allergen nickel triggers a unique inflammatory and proangiogenic gene expression pattern via activation of NF-kappaB and hypoxia-inducible factor-1alpha. J Immunol. 2007 Mar 1;178(5):3198-207.