Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTMKKE3W)

• DOT Name: Homeobox protein TGIF2 (TGIF2)
• Synonyms: 5'-TG-3'-interacting factor 2; TGF-beta-induced transcription factor 2; TGFB-induced factor 2
• Gene Name: TGIF2
• Related Disease:
  Epithelial ovarian cancer
  Gastric cancer
  Glioblastoma multiforme
  Glioma
  Holoprosencephaly
  Medulloblastoma
  Non-small-cell lung cancer
  Ovarian cancer
  Ovarian neoplasm
  Skin cancer
  Stomach cancer
  Neoplasm
  Bone osteosarcoma
  Osteosarcoma
• UniProt ID: TGIF2_HUMAN
• Pfam ID: PF05920
• Sequence:
  MSDSDLGEDEGLLSLAGKRKRRGNLPKESVKILRDWLYLHRYNAYPSEQEKLSLSGQTNL
  SVLQICNWFINARRRLLPDMLRKDGKDPNQFTISRRGGKASDVALPRGSSPSVLAVSVPA
  PTNVLSLSVCSMPLHSGQGEKPAAPFPRGELESPKPLVTPGSTLTLLTRAEAGSPTGGLF
  NTPPPTPPEQDKEDFSSFQLLVEVALQRAAEMELQKQQDPSLPLLHTPIPLVSENPQ
• Function: Transcriptional repressor, which probably repress transcription by binding directly the 5'-CTGTCAA-3' DNA sequence or by interacting with TGF-beta activated SMAD proteins. Probably represses transcription via the recruitment of histone deacetylase proteins.
• Tissue Specificity: Widely expressed. Highly expressed in heart, kidney and testis. Weakly expressed in brain and prostate.
• KEGG Pathway: TGF-beta sig.ling pathway (hsa04350)
• Reactome Pathway:
  SMAD2/SMAD3 (R-HSA-2173796)
  Downregulation of SMAD2/3 (R-HSA-2173795)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[1]
Gastric cancer	DISXGOUK	Strong	Biomarker	[2]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[3]
Glioma	DIS5RPEH	Strong	Biomarker	[4]
Holoprosencephaly	DISR35EC	Strong	Biomarker	[5]
Medulloblastoma	DISZD2ZL	Strong	Altered Expression	[6]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[7]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[1]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[1]
Skin cancer	DISTM18U	Strong	Biomarker	[8]
Stomach cancer	DISKIJSX	Strong	Biomarker	[2]
Neoplasm	DISZKGEW	Disputed	Altered Expression	[9]
Bone osteosarcoma	DIST1004	Limited	Altered Expression	[10]
Osteosarcoma	DISLQ7E2	Limited	Altered Expression	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Homeobox protein TGIF2 (TGIF2).	[11]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Homeobox protein TGIF2 (TGIF2).	[12]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Homeobox protein TGIF2 (TGIF2).	[13]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Homeobox protein TGIF2 (TGIF2).	[14]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Homeobox protein TGIF2 (TGIF2).	[15]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Homeobox protein TGIF2 (TGIF2).	[16]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Homeobox protein TGIF2 (TGIF2).	[17]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Homeobox protein TGIF2 (TGIF2).	[18]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Homeobox protein TGIF2 (TGIF2).	[19]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Homeobox protein TGIF2 (TGIF2).	[21]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Homeobox protein TGIF2 (TGIF2).	[23]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Homeobox protein TGIF2 (TGIF2).	[24]
Glyphosate	DM0AFY7	Investigative	Glyphosate increases the expression of Homeobox protein TGIF2 (TGIF2).	[25]
QUERCITRIN	DM1DH96	Investigative	QUERCITRIN decreases the expression of Homeobox protein TGIF2 (TGIF2).	[26]

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 affects the methylation of Homeobox protein TGIF2 (TGIF2).	[20]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Homeobox protein TGIF2 (TGIF2).	[22]

References

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• [2] MicroRNA-34a inhibits tumor invasion and metastasis in gastric cancer by targeting Tgif2.Int J Clin Exp Pathol. 2015 Aug 1;8(8):8921-8. eCollection 2015.
• [3] Polycomb complex mediated epigenetic reprogramming alters TGF- signaling via a novel EZH2/miR-490/TGIF2 axis thereby inducing migration and EMT potential in glioblastomas.Int J Cancer. 2019 Sep 1;145(5):1254-1269. doi: 10.1002/ijc.32360. Epub 2019 May 10.
• [4] MiR-129-5p inhibits glioma cell progression invitro and invivo by targeting TGIF2.J Cell Mol Med. 2018 Apr;22(4):2357-2367. doi: 10.1111/jcmm.13529. Epub 2018 Feb 12.
• [5] Tgif1 and Tgif2 Repress Expression of the RabGAP Evi5l.Mol Cell Biol. 2017 Feb 15;37(5):e00527-16. doi: 10.1128/MCB.00527-16. Print 2017 Mar 1.
• [6] Identification of FoxR2 as an oncogene in medulloblastoma.Cancer Res. 2014 Apr 15;74(8):2351-61. doi: 10.1158/0008-5472.CAN-13-1523. Epub 2014 Mar 5.
• [7] Long noncoding RNA SNHG7 contributes to cell proliferation, migration, invasion and epithelial to mesenchymal transition in non-small cell lung cancer by regulating miR-449a/TGIF2 axis.Thorac Cancer. 2020 Feb;11(2):264-276. doi: 10.1111/1759-7714.13245. Epub 2019 Dec 3.
• [8] Down-Regulation of miR-148a Promotes Metastasis by DNA Methylation and is Associated with Prognosis of Skin Cancer by Targeting TGIF2.Med Sci Monit. 2015 Dec 6;21:3798-805. doi: 10.12659/msm.894826.
• [9] Regulation of miRNA-29c and its downstream pathways in preneoplastic progression of triple-negative breast cancer.Oncotarget. 2017 Mar 21;8(12):19645-19660. doi: 10.18632/oncotarget.14902.
• [10] miR-34 inhibits growth and promotes apoptosis of osteosarcoma in nude mice through targetly regulating TGIF2 expression.Biosci Rep. 2018 Jun 12;38(3):BSR20180078. doi: 10.1042/BSR20180078. Print 2018 Jun 29.
• [11] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [12] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [13] 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.
• [14] 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.
• [15] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [16] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [17] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [18] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [19] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [20] 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.
• [21] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [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] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [24] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [25] Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.
• [26] Molecular mechanisms of quercitrin-induced apoptosis in non-small cell lung cancer. Arch Med Res. 2014 Aug;45(6):445-54.