Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTVWPZ8B)

• DOT Name: Transcription factor 7-like 2 (TCF7L2)
• Synonyms: HMG box transcription factor 4; T-cell-specific transcription factor 4; T-cell factor 4; TCF-4; hTCF-4
• Gene Name: TCF7L2
• Related Disease:
  Complex neurodevelopmental disorder
  Intellectual disability
  Congenital glaucoma
• UniProt ID: TF7L2_HUMAN
• PDB ID: 1JDH; 1JPW; 2GL7
• Pfam ID: PF08347 ; PF00505
• Sequence:
  MPQLNGGGGDDLGANDELISFKDEGEQEEKSSENSSAERDLADVKSSLVNESETNQNSSS
  DSEAERRPPPRSESFRDKSRESLEEAAKRQDGGLFKGPPYPGYPFIMIPDLTSPYLPNGS
  LSPTARTLHFQSGSTHYSAYKTIEHQIAVQYLQMKWPLLDVQAGSLQSRQALKDARSPSP
  AHIVSNKVPVVQHPHHVHPLTPLITYSNEHFTPGNPPPHLPADVDPKTGIPRPPHPPDIS
  PYYPLSPGTVGQIPHPLGWLVPQQGQPVYPITTGGFRHPYPTALTVNASMSRFPPHMVPP
  HHTLHTTGIPHPAIVTPTVKQESSQSDVGSLHSSKHQDSKKEEEKKKPHIKKPLNAFMLY
  MKEMRAKVVAECTLKESAAINQILGRRWHALSREEQAKYYELARKERQLHMQLYPGWSAR
  DNYGKKKKRKRDKQPGETNEHSECFLNPCLSLPPITDLSAPKKCRARFGLDQQNNWCGPC
  RRKKKCVRYIQGEGSCLSPPSSDGSLLDSPPPSPNLLGSPPRDAKSQTEQTQPLSLSLKP
  DPLAHLSMMPPPPALLLAEATHKASALCPNGALDLPPAALQPAAPSSSIAQPSTSSLHSH
  SSLAGTQPQPLSLVTKSLE
• Function: Participates in the Wnt signaling pathway and modulates MYC expression by binding to its promoter in a sequence-specific manner. Acts as a repressor in the absence of CTNNB1, and as activator in its presence. Activates transcription from promoters with several copies of the Tcf motif 5'-CCTTTGATC-3' in the presence of CTNNB1. TLE1, TLE2, TLE3 and TLE4 repress transactivation mediated by TCF7L2/TCF4 and CTNNB1. Expression of dominant-negative mutants results in cell-cycle arrest in G1. Necessary for the maintenance of the epithelial stem-cell compartment of the small intestine.
• Tissue Specificity: Detected in epithelium from small intestine, with the highest expression at the top of the crypts and a gradient of expression from crypt to villus. Detected in colon epithelium and colon cancer, and in epithelium from mammary gland and carcinomas derived therefrom.
• KEGG Pathway:
  Wnt sig.ling pathway (hsa04310)
  Hippo sig.ling pathway (hsa04390)
  Adherens junction (hsa04520)
  Melanogenesis (hsa04916)
  Cushing syndrome (hsa04934)
  Alcoholic liver disease (hsa04936)
  Salmonella infection (hsa05132)
  Human papillomavirus infection (hsa05165)
  Kaposi sarcoma-associated herpesvirus infection (hsa05167)
  Pathways in cancer (hsa05200)
  Colorectal cancer (hsa05210)
  Endometrial cancer (hsa05213)
  Prostate cancer (hsa05215)
  Thyroid cancer (hsa05216)
  Basal cell carcinoma (hsa05217)
  Acute myeloid leukemia (hsa05221)
  Breast cancer (hsa05224)
  Hepatocellular carcinoma (hsa05225)
  Gastric cancer (hsa05226)
  Arrhythmogenic right ventricular cardiomyopathy (hsa05412)
• Reactome Pathway:
  Deactivation of the beta-catenin transactivating complex (R-HSA-3769402)
  Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) (R-HSA-381771)
  Ca2+ pathway (R-HSA-4086398)
  Binding of TCF/LEF (R-HSA-4411364)
  Repression of WNT target genes (R-HSA-4641265)
  Signaling by TCF7L2 mutants (R-HSA-5339700)
  Transcriptional Regulation by VENTX (R-HSA-8853884)
  RUNX3 regulates WNT signaling (R-HSA-8951430)
  Formation of definitive endoderm (R-HSA-9823730)
  Formation of the beta-catenin (R-HSA-201722)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Complex neurodevelopmental disorder	DISB9AFI	Definitive	Autosomal dominant	[1]
Intellectual disability	DISMBNXP	Moderate	Autosomal dominant	[2]
Congenital glaucoma	DISHN3GO	Limited	Unknown	[2]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Topotecan	DMP6G8T	Approved	Transcription factor 7-like 2 (TCF7L2) affects the response to substance of Topotecan.	[29]

4 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Transcription factor 7-like 2 (TCF7L2).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Transcription factor 7-like 2 (TCF7L2).	[20]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Transcription factor 7-like 2 (TCF7L2).	[22]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the methylation of Transcription factor 7-like 2 (TCF7L2).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Transcription factor 7-like 2 (TCF7L2).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Transcription factor 7-like 2 (TCF7L2).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Transcription factor 7-like 2 (TCF7L2).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Transcription factor 7-like 2 (TCF7L2).	[7]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Transcription factor 7-like 2 (TCF7L2).	[8]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Transcription factor 7-like 2 (TCF7L2).	[9]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Transcription factor 7-like 2 (TCF7L2).	[10]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Transcription factor 7-like 2 (TCF7L2).	[11]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Transcription factor 7-like 2 (TCF7L2).	[12]
Menadione	DMSJDTY	Approved	Menadione decreases the expression of Transcription factor 7-like 2 (TCF7L2).	[13]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of Transcription factor 7-like 2 (TCF7L2).	[14]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the expression of Transcription factor 7-like 2 (TCF7L2).	[15]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of Transcription factor 7-like 2 (TCF7L2).	[16]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Transcription factor 7-like 2 (TCF7L2).	[11]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate increases the expression of Transcription factor 7-like 2 (TCF7L2).	[17]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Transcription factor 7-like 2 (TCF7L2).	[18]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Transcription factor 7-like 2 (TCF7L2).	[12]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene increases the expression of Transcription factor 7-like 2 (TCF7L2).	[19]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Transcription factor 7-like 2 (TCF7L2).	[21]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Transcription factor 7-like 2 (TCF7L2).	[24]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Transcription factor 7-like 2 (TCF7L2).	[25]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Transcription factor 7-like 2 (TCF7L2).	[26]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of Transcription factor 7-like 2 (TCF7L2).	[27]
geraniol	DMS3CBD	Investigative	geraniol decreases the expression of Transcription factor 7-like 2 (TCF7L2).	[28]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [3] Nuclear and Mitochondrial DNA Methylation Patterns Induced by Valproic Acid in Human Hepatocytes. Chem Res Toxicol. 2017 Oct 16;30(10):1847-1854. doi: 10.1021/acs.chemrestox.7b00171. Epub 2017 Sep 13.
• [4] 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.
• [5] 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.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Real-time monitoring of cisplatin-induced cell death. PLoS One. 2011;6(5):e19714. doi: 10.1371/journal.pone.0019714. Epub 2011 May 16.
• [8] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [9] Quercetin inhibit human SW480 colon cancer growth in association with inhibition of cyclin D1 and survivin expression through Wnt/beta-catenin signaling pathway. Cancer Invest. 2009 Jul;27(6):604-12. doi: 10.1080/07357900802337191.
• [10] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [11] Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNF-mediated hepatotoxicity. Toxicol Sci. 2014 Jul;140(1):144-59. doi: 10.1093/toxsci/kfu072. Epub 2014 Apr 20.
• [12] 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.
• [13] Vitamin K3 (menadione) suppresses epithelial-mesenchymal-transition and Wnt signaling pathway in human colorectal cancer cells. Chem Biol Interact. 2019 Aug 25;309:108725. doi: 10.1016/j.cbi.2019.108725. Epub 2019 Jun 22.
• [14] Induction of heme oxygenase-1 by cobalt protoporphyrin enhances the antitumour effect of bortezomib in adult T-cell leukaemia cells. Br J Cancer. 2007 Oct 22;97(8):1099-105. doi: 10.1038/sj.bjc.6604003. Epub 2007 Sep 25.
• [15] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [16] Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
• [17] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [18] Fluorinated N,N-dialkylaminostilbenes for Wnt pathway inhibition and colon cancer repression. J Med Chem. 2011 Mar 10;54(5):1288-97. doi: 10.1021/jm101248v. Epub 2011 Feb 3.
• [19] Regulation of aryl hydrocarbon receptor function by selective estrogen receptor modulators. Mol Endocrinol. 2010 Jan;24(1):33-46.
• [20] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [21] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [22] 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.
• [23] 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.
• [24] 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.
• [25] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [26] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [27] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.
• [28] Geraniol suppresses prostate cancer growth through down-regulation of E2F8. Cancer Med. 2016 Oct;5(10):2899-2908.
• [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.