Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTTUTF0O)

• DOT Name: Transcription factor 7-like 1 (TCF7L1)
• Synonyms: HMG box transcription factor 3; TCF-3
• Gene Name: TCF7L1
• Related Disease:
  Carcinoma of liver and intrahepatic biliary tract
  Liver cancer
  Acute lymphocytic leukaemia
  Advanced cancer
  B-cell acute lymphoblastic leukaemia
  Burkitt lymphoma
  Cervical carcinoma
  Childhood acute lymphoblastic leukemia
  Desmoid tumour
  Gastric cancer
  Germ cell tumor
  Marinesco-Sjogren syndrome
  Neoplasm
  Nongerminomatous germ cell tumor
  Stomach cancer
  Hepatocellular carcinoma
  leukaemia
  Leukemia
  Thyroid gland carcinoma
  Thyroid tumor
  Colorectal carcinoma
  Cutaneous squamous cell carcinoma
• UniProt ID: TF7L1_HUMAN
• Pfam ID: PF08347 ; PF00505
• Sequence:
  MPQLGGGGGGGGGGSGGGGGSSAGAAGGGDDLGANDELIPFQDEGGEEQEPSSDSASAQR
  DLDEVKSSLVNESENQSSSSDSEAERRPQPVRDTFQKPRDYFAEVRRPQDSAFFKGPPYP
  GYPFLMIPDLSSPYLSNGPLSPGGARTYLQMKWPLLDVPSSATVKDTRSPSPAHLSNKVP
  VVQHPHHMHPLTPLITYSNDHFSPGSPPTHLSPEIDPKTGIPRPPHPSELSPYYPLSPGA
  VGQIPHPLGWLVPQQGQPMYSLPPGGFRHPYPALAMNASMSSLVSSRFSPHMVAPAHPGL
  PTSGIPHPAIVSPIVKQEPAPPSLSPAVSVKSPVTVKKEEEKKPHVKKPLNAFMLYMKEM
  RAKVVAECTLKESAAINQILGRKWHNLSREEQAKYYELARKERQLHSQLYPTWSARDNYG
  KKKKRKREKQLSQTQSQQQVQEAEGALASKSKKPCVQYLPPEKPCDSPASSHGSMLDSPA
  TPSAALASPAAPAATHSEQAQPLSLTTKPETRAQLALHSAAFLSAKAAASSSGQMGSQPP
  LLSRPLPLGSMPTALLASPPSFPATLHAHQALPVLQAQPLSLVTKSAH
• Function: Participates in the Wnt signaling pathway. Binds to DNA and acts as a repressor in the absence of CTNNB1, and as an activator in its presence. Necessary for the terminal differentiation of epidermal cells, the formation of keratohyalin granules and the development of the barrier function of the epidermis. Down-regulates NQO1, leading to increased mitomycin c resistance.
• Tissue Specificity: Detected in hair follicles and skin keratinocytes, and at lower levels in stomach epithelium.
• 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)
  Ca2+ pathway (R-HSA-4086398)
  Binding of TCF/LEF (R-HSA-4411364)
  Repression of WNT target genes (R-HSA-4641265)
  RUNX3 regulates WNT signaling (R-HSA-8951430)
  Formation of the beta-catenin (R-HSA-201722)

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Definitive	Biomarker	[1]
Liver cancer	DISDE4BI	Definitive	Biomarker	[1]
Acute lymphocytic leukaemia	DISPX75S	Strong	Genetic Variation	[2]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[3]
B-cell acute lymphoblastic leukaemia	DISKLOKC	Strong	Genetic Variation	[4]
Burkitt lymphoma	DIS9D5XU	Strong	Biomarker	[5]
Cervical carcinoma	DIST4S00	Strong	Genetic Variation	[6]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Strong	Biomarker	[4]
Desmoid tumour	DISGX357	Strong	Altered Expression	[7]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[3]
Germ cell tumor	DIS62070	Strong	Altered Expression	[8]
Marinesco-Sjogren syndrome	DISKEU0B	Strong	Biomarker	[9]
Neoplasm	DISZKGEW	Strong	Altered Expression	[10]
Nongerminomatous germ cell tumor	DISQOQJU	Strong	Biomarker	[8]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[3]
Hepatocellular carcinoma	DIS0J828	moderate	Altered Expression	[1]
leukaemia	DISS7D1V	moderate	Biomarker	[11]
Leukemia	DISNAKFL	moderate	Biomarker	[11]
Thyroid gland carcinoma	DISMNGZ0	moderate	Biomarker	[12]
Thyroid tumor	DISLVKMD	moderate	Biomarker	[12]
Colorectal carcinoma	DIS5PYL0	Limited	Altered Expression	[13]
Cutaneous squamous cell carcinoma	DIS3LXUG	Limited	Altered Expression	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Transcription factor 7-like 1 (TCF7L1).	[14]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Transcription factor 7-like 1 (TCF7L1).	[15]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Transcription factor 7-like 1 (TCF7L1).	[16]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Transcription factor 7-like 1 (TCF7L1).	[17]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Transcription factor 7-like 1 (TCF7L1).	[18]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Transcription factor 7-like 1 (TCF7L1).	[19]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Transcription factor 7-like 1 (TCF7L1).	[20]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Transcription factor 7-like 1 (TCF7L1).	[21]
Malathion	DMXZ84M	Approved	Malathion increases the expression of Transcription factor 7-like 1 (TCF7L1).	[22]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Transcription factor 7-like 1 (TCF7L1).	[23]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Transcription factor 7-like 1 (TCF7L1).	[24]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Transcription factor 7-like 1 (TCF7L1).	[25]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Transcription factor 7-like 1 (TCF7L1).	[27]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Transcription factor 7-like 1 (TCF7L1).	[29]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Transcription factor 7-like 1 (TCF7L1).	[30]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Transcription factor 7-like 1 (TCF7L1).	[26]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Transcription factor 7-like 1 (TCF7L1).	[28]

References

• [1] Tcf7l1 Acts as a Suppressor for the Self-Renewal of Liver Cancer Stem Cells and Is Regulated by IGF/MEK/ERK Signaling Independent of -Catenin.Stem Cells. 2019 Nov;37(11):1389-1400. doi: 10.1002/stem.3063. Epub 2019 Aug 26.
• [2] PKC and PKM are overexpressed in TCF3-rearranged paediatric acute lymphoblastic leukaemia and are associated with increased thiopurine sensitivity.Leukemia. 2015 Feb;29(2):304-11. doi: 10.1038/leu.2014.210. Epub 2014 Jul 3.
• [3] TCF7L1 indicates prognosis and promotes proliferation through activation of Keap1/NRF2 in gastric cancer.Acta Biochim Biophys Sin (Shanghai). 2019 Apr 1;51(4):375-385. doi: 10.1093/abbs/gmz015.
• [4] Promoter analysis of TFPT (FB1), a molecular partner of TCF3 (E2A) in childhood acute lymphoblastic leukemia.Biochem Biophys Res Commun. 2001 Nov 16;288(5):1250-7. doi: 10.1006/bbrc.2001.5906.
• [5] Oncogenic mechanisms in Burkitt lymphoma.Cold Spring Harb Perspect Med. 2014 Feb 1;4(2):a014282. doi: 10.1101/cshperspect.a014282.
• [6] Genome-wide association study of cervical cancer suggests a role for ARRDC3 gene in human papillomavirus infection.Hum Mol Genet. 2019 Jan 15;28(2):341-348. doi: 10.1093/hmg/ddy390.
• [7] Tcf-3 expression and beta-catenin mediated transcriptional activation in aggressive fibromatosis (desmoid tumour).Br J Cancer. 2001 Jul 6;85(1):98-101. doi: 10.1054/bjoc.2001.1857.
• [8] Wnt suppressor and stem cell regulator TCF7L1 is a sensitive immunohistochemical marker to differentiate testicular seminoma from non-seminomatous germ cell tumor.Exp Mol Pathol. 2019 Oct;110:104293. doi: 10.1016/j.yexmp.2019.104293. Epub 2019 Aug 2.
• [9] TCF-3, 4 protein expression correlates with beta-catenin expression in MSS and MSI-H colorectal cancer from HNPCC patients but not in sporadic colorectal cancers.Int J Colorectal Dis. 2010 Aug;25(8):931-9. doi: 10.1007/s00384-010-0959-9. Epub 2010 Jun 8.
• [10] TCF7L1 promotes skin tumorigenesis independently of -catenin through induction of LCN2.Elife. 2017 May 3;6:e23242. doi: 10.7554/eLife.23242.
• [11] Poly (ADP-ribose) polymerase inhibitors selectively induce cytotoxicity in TCF3-HLF-positive leukemic cells.Cancer Lett. 2017 Feb 1;386:131-140. doi: 10.1016/j.canlet.2016.11.021. Epub 2016 Nov 25.
• [12] Cancer-related genes transcriptionally induced by the fungicide penconazole.Toxicol In Vitro. 2014 Feb;28(1):125-30. doi: 10.1016/j.tiv.2013.06.006. Epub 2013 Jun 27.
• [13] TCF7L1 recruits CtBP and HDAC1 to repress DICKKOPF4 gene expression in human colorectal cancer cells.Biochem Biophys Res Commun. 2017 Jun 3;487(3):716-722. doi: 10.1016/j.bbrc.2017.04.123. Epub 2017 Apr 25.
• [14] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [15] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [16] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [17] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [18] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [19] A comprehensive analysis of Wnt/beta-catenin signaling pathway-related genes and crosstalk pathways in the treatment of As2O3 in renal cancer. Ren Fail. 2018 Nov;40(1):331-339.
• [20] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [21] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [22] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [23] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [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] 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.
• [26] 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.
• [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] 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.
• [29] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [30] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.