Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2KSZ9B)

• DOT Name: Transducin-like enhancer protein 2 (TLE2)
• Synonyms: Enhancer of split groucho-like protein 2; ESG2
• Gene Name: TLE2
• Related Disease:
  Advanced cancer
  Astrocytoma
  Carcinoma of esophagus
  Esophageal cancer
  Neoplasm of esophagus
  Adult lymphoma
  Lymphoma
  Pediatric lymphoma
  Post-traumatic stress disorder
• UniProt ID: TLE2_HUMAN
• Pfam ID: PF03920 ; PF00400
• Sequence:
  MYPQGRHPTPLQSGQPFKFSILEICDRIKEEFQFLQAQYHSLKLECEKLASEKTEMQRHY
  VMYYEMSYGLNIEMHKQAEIVKRLSGICAQIIPFLTQEHQQQVLQAVERAKQVTVGELNS
  LIGQQLQPLSHHAPPVPLTPRPAGLVGGSATGLLALSGALAAQAQLAAAVKEDRAGVEAE
  GSRVERAPSRSASPSPPESLVEEERPSGPGGGGKQRADEKEPSGPYESDEDKSDYNLVVD
  EDQPSEPPSPATTPCGKVPICIPARRDLVDSPASLASSLGSPLPRAKELILNDLPASTPA
  SKSCDSSPPQDASTPGPSSASHLCQLAAKPAPSTDSVALRSPLTLSSPFTTSFSLGSHST
  LNGDLSVPSSYVSLHLSPQVSSSVVYGRSPVMAFESHPHLRGSSVSSSLPSIPGGKPAYS
  FHVSADGQMQPVPFPSDALVGAGIPRHARQLHTLAHGEVVCAVTISGSTQHVYTGGKGCV
  KVWDVGQPGAKTPVAQLDCLNRDNYIRSCKLLPDGRSLIVGGEASTLSIWDLAAPTPRIK
  AELTSSAPACYALAVSPDAKVCFSCCSDGNIVVWDLQNQTMVRQFQGHTDGASCIDISDY
  GTRLWTGGLDNTVRCWDLREGRQLQQHDFSSQIFSLGHCPNQDWLAVGMESSNVEILHVR
  KPEKYQLHLHESCVLSLKFASCGRWFVSTGKDNLLNAWRTPYGASIFQSKESSSVLSCDI
  SRNNKYIVTGSGDKKATVYEVVY
• 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: In all tissues examined, mostly in heart, brain, and muscle.
• KEGG Pathway:
  Wnt sig.ling pathway (hsa04310)
  Notch sig.ling pathway (hsa04330)
• Reactome Pathway:
  NOTCH1 Intracellular Domain Regulates Transcription (R-HSA-2122947)
  Deactivation of the beta-catenin transactivating complex (R-HSA-3769402)
  Repression of WNT target genes (R-HSA-4641265)
  Formation of the beta-catenin (R-HSA-201722)

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Astrocytoma	DISL3V18	Strong	Altered Expression	[2]
Carcinoma of esophagus	DISS6G4D	Strong	Altered Expression	[3]
Esophageal cancer	DISGB2VN	Strong	Altered Expression	[3]
Neoplasm of esophagus	DISOLKAQ	Strong	Altered Expression	[3]
Adult lymphoma	DISK8IZR	Limited	Altered Expression	[4]
Lymphoma	DISN6V4S	Limited	Altered Expression	[4]
Pediatric lymphoma	DIS51BK2	Limited	Altered Expression	[4]
Post-traumatic stress disorder	DISHL1EY	Limited	Biomarker	[5]

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 2 (TLE2).	[6]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Transducin-like enhancer protein 2 (TLE2).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Transducin-like enhancer protein 2 (TLE2).	[19]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Transducin-like enhancer protein 2 (TLE2).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Transducin-like enhancer protein 2 (TLE2).	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Transducin-like enhancer protein 2 (TLE2).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Transducin-like enhancer protein 2 (TLE2).	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Transducin-like enhancer protein 2 (TLE2).	[9]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Transducin-like enhancer protein 2 (TLE2).	[11]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Transducin-like enhancer protein 2 (TLE2).	[12]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Transducin-like enhancer protein 2 (TLE2).	[13]
Selenium	DM25CGV	Approved	Selenium increases the expression of Transducin-like enhancer protein 2 (TLE2).	[14]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Transducin-like enhancer protein 2 (TLE2).	[15]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Transducin-like enhancer protein 2 (TLE2).	[16]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Transducin-like enhancer protein 2 (TLE2).	[17]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Transducin-like enhancer protein 2 (TLE2).	[18]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Transducin-like enhancer protein 2 (TLE2).	[20]

References

• [1] ANLN and TLE2 in Muscle Invasive Bladder Cancer: A Functional and Clinical Evaluation Based on In Silico and In Vitro Data.Cancers (Basel). 2019 Nov 21;11(12):1840. doi: 10.3390/cancers11121840.
• [2] Exploring the distinctive biological characteristics of pilocytic and low-grade diffuse astrocytomas using microarray gene expression profiles.J Neuropathol Exp Neurol. 2006 Aug;65(8):794-807. doi: 10.1097/01.jnen.0000228203.12292.a1.
• [3] NDRG1 overexpression promotes the progression of esophageal squamous cell carcinoma through modulating Wnt signaling pathway.Cancer Biol Ther. 2016 Sep;17(9):943-54. doi: 10.1080/15384047.2016.1210734. Epub 2016 Jul 14.
• [4] 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.
• [5] The anxiolytic-like effects of ginsenoside Rg2 on an animal model of PTSD.Psychiatry Res. 2019 Sep;279:130-137. doi: 10.1016/j.psychres.2018.12.034. Epub 2018 Dec 6.
• [6] 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.
• [7] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [8] 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.
• [9] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [10] 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.
• [11] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [12] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [13] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [14] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [15] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [16] Endometrial receptivity is affected in women with high circulating progesterone levels at the end of the follicular phase: a functional genomics analysis. Hum Reprod. 2011 Jul;26(7):1813-25.
• [17] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [18] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [19] 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.
• [20] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [21] 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.
• [22] 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.