Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTTOT7A9)

• DOT Name: T-box transcription factor TBX2 (TBX2)
• Synonyms: T-box protein 2
• Gene Name: TBX2
• Related Disease:
  Advanced cancer
  Gastric cancer
  Lung adenocarcinoma
  Lung cancer
  Lung carcinoma
  Stomach cancer
  Adrenocortical carcinoma
  Alzheimer disease
  Alzheimer disease 3
  Bladder cancer
  Bone osteosarcoma
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Coloboma
  Colorectal carcinoma
  Congenital diaphragmatic hernia
  Metastatic prostate carcinoma
  Neoplasm
  Neuroblastoma
  Non-small-cell lung cancer
  Osteosarcoma
  Ovarian serous adenocarcinoma
  Pancreatic cancer
  Persistent truncus arteriosus
  Prostate cancer
  Prostate carcinoma
  Rhabdomyosarcoma
  Urinary bladder cancer
  Urinary bladder neoplasm
  Ventricular septal defect
  Vertebral anomalies and variable endocrine and T-cell dysfunction
  Hepatocellular carcinoma
  High blood pressure
  Melanoma
  Acute respiratory failure
  Adult glioblastoma
  Arrhythmia
  Astrocytoma
  Congenital heart disease
  Glioblastoma multiforme
  Malignant tumor of nasopharynx
  Metastatic malignant neoplasm
  Nasopharyngeal carcinoma
  Rheumatic fever
• UniProt ID: TBX2_HUMAN
• Pfam ID: PF00907 ; PF12598 ; PF20627
• Sequence:
  MREPALAASAMAYHPFHAPRPADFPMSAFLAAAQPSFFPALALPPGALAKPLPDPGLAGA
  AAAAAAAAAAAEAGLHVSALGPHPPAAHLRSLKSLEPEDEVEDDPKVTLEAKELWDQFHK
  LGTEMVITKSGRRMFPPFKVRVSGLDKKAKYILLMDIVAADDCRYKFHNSRWMVAGKADP
  EMPKRMYIHPDSPATGEQWMAKPVAFHKLKLTNNISDKHGFTILNSMHKYQPRFHIVRAN
  DILKLPYSTFRTYVFPETDFIAVTAYQNDKITQLKIDNNPFAKGFRDTGNGRREKRKQLT
  LPSLRLYEEHCKPERDGAESDASSCDPPPAREPPTSPGAAPSPLRLHRARAEEKSCAADS
  DPEPERLSEERAGAPLGRSPAPDSASPTRLTEPERARERRSPERGKEPAESGGDGPFGLR
  SLEKERAEARRKDEGRKEAAEGKEQGLAPLVVQTDSASPLGAGHLPGLAFSSHLHGQQFF
  GPLGAGQPLFLHPGQFTMGPGAFSAMGMGHLLASVAGGGNGGGGGPGTAAGLDAGGLGPA
  ASAASTAAPFPFHLSQHMLASQGIPMPTFGGLFPYPYTYMAAAAAAASALPATSAAAAAA
  AAAGSLSRSPFLGSARPRLRFSPYQIPVTIPPSTSLLTTGLASEGSKAAGGNSREPSPLP
  ELALRKVGAPSRGALSPSGSAKEAANELQSIQRLVSGLESQRALSPGRESPK
• Function: Transcription factor which acts as a transcriptional repressor. May also function as a transcriptional activator. Binds to the palindromic T site 5'-TTCACACCTAGGTGTGAA-3' DNA sequence, or a half-site, which are present in the regulatory region of several genes. Required for cardiac atrioventricular canal formation. May cooperate with NKX2.5 to negatively modulate expression of NPPA/ANF in the atrioventricular canal. May play a role as a positive regulator of TGFB2 expression, perhaps acting in concert with GATA4 in the developing outflow tract myocardium. Plays a role in limb pattern formation. Acts as a transcriptional repressor of ADAM10 gene expression, perhaps in concert with histone deacetylase HDAC1 as cofactor. Involved in branching morphogenesis in both developing lungs and adult mammary glands, via negative modulation of target genes; acting redundantly with TBX3. Required, together with TBX3, to maintain cell proliferation in the embryonic lung mesenchyme; perhaps acting downstream of SHH, BMP and TGFbeta signaling. Involved in modulating early inner ear development, acting independently of, and also redundantly with TBX3, in different subregions of the developing ear. Acts as a negative regulator of PML function in cellular senescence. Acts as a negative regulator of expression of CDKN1A/p21, IL33 and CCN4; repression of CDKN1A is enhanced in response to UV-induced stress, perhaps as a result of phosphorylation by p38 MAPK. Negatively modulates expression of CDKN2A/p14ARF and CDH1/E-cadherin. Plays a role in induction of the epithelial-mesenchymal transition (EMT). Plays a role in melanocyte proliferation, perhaps via regulation of cyclin CCND1. Involved in melanogenesis, acting via negative modulation of expression of DHICA oxidase/TYRP1 and P protein/OCA2. Involved in regulating retinal pigment epithelium (RPE) cell proliferation, perhaps via negatively modulating transcription of the transcription factor CEBPD.
• Tissue Specificity: Expressed primarily in adult in kidney, lung, and placenta. Weak expression in heart and ovary.

Molecular Interaction Atlas (MIA) of This DOT

45 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Definitive	Altered Expression	[1]
Gastric cancer	DISXGOUK	Definitive	Biomarker	[2]
Lung adenocarcinoma	DISD51WR	Definitive	Altered Expression	[3]
Lung cancer	DISCM4YA	Definitive	Biomarker	[3]
Lung carcinoma	DISTR26C	Definitive	Biomarker	[3]
Stomach cancer	DISKIJSX	Definitive	Biomarker	[2]
Adrenocortical carcinoma	DISZF4HX	Strong	Altered Expression	[4]
Alzheimer disease	DISF8S70	Strong	Altered Expression	[5]
Alzheimer disease 3	DISVT69G	Strong	Altered Expression	[5]
Bladder cancer	DISUHNM0	Strong	Posttranslational Modification	[6]
Bone osteosarcoma	DIST1004	Strong	Altered Expression	[7]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[8]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[9]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[10]
Coloboma	DISP39N5	Strong	Genetic Variation	[11]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[12]
Congenital diaphragmatic hernia	DIS0IPVU	Strong	Altered Expression	[13]
Metastatic prostate carcinoma	DISVBEZ9	Strong	Biomarker	[14]
Neoplasm	DISZKGEW	Strong	Altered Expression	[2]
Neuroblastoma	DISVZBI4	Strong	Altered Expression	[5]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[15]
Osteosarcoma	DISLQ7E2	Strong	Altered Expression	[7]
Ovarian serous adenocarcinoma	DISSU72Z	Strong	Altered Expression	[16]
Pancreatic cancer	DISJC981	Strong	Altered Expression	[17]
Persistent truncus arteriosus	DISRZ8EA	Strong	Genetic Variation	[18]
Prostate cancer	DISF190Y	Strong	Biomarker	[14]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[14]
Rhabdomyosarcoma	DISNR7MS	Strong	Biomarker	[19]
Urinary bladder cancer	DISDV4T7	Strong	Posttranslational Modification	[6]
Urinary bladder neoplasm	DIS7HACE	Strong	Posttranslational Modification	[6]
Ventricular septal defect	DISICO41	Strong	Biomarker	[20]
Vertebral anomalies and variable endocrine and T-cell dysfunction	DISG0CJK	Strong	Autosomal dominant	[21]
Hepatocellular carcinoma	DIS0J828	moderate	Posttranslational Modification	[22]
High blood pressure	DISY2OHH	moderate	Genetic Variation	[23]
Melanoma	DIS1RRCY	Disputed	Biomarker	[24]
Acute respiratory failure	DIS5KQ5Y	Limited	Altered Expression	[25]
Adult glioblastoma	DISVP4LU	Limited	Biomarker	[26]
Arrhythmia	DISFF2NI	Limited	Altered Expression	[27]
Astrocytoma	DISL3V18	Limited	Altered Expression	[26]
Congenital heart disease	DISQBA23	Limited	Genetic Variation	[28]
Glioblastoma multiforme	DISK8246	Limited	Biomarker	[26]
Malignant tumor of nasopharynx	DISTGIGF	Limited	Altered Expression	[29]
Metastatic malignant neoplasm	DIS86UK6	Limited	Altered Expression	[9]
Nasopharyngeal carcinoma	DISAOTQ0	Limited	Altered Expression	[29]
Rheumatic fever	DISLUF66	Limited	Altered Expression	[25]

3 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 T-box transcription factor TBX2 (TBX2).	[30]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of T-box transcription factor TBX2 (TBX2).	[35]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of T-box transcription factor TBX2 (TBX2).	[41]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of T-box transcription factor TBX2 (TBX2).	[31]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of T-box transcription factor TBX2 (TBX2).	[32]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of T-box transcription factor TBX2 (TBX2).	[33]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of T-box transcription factor TBX2 (TBX2).	[34]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of T-box transcription factor TBX2 (TBX2).	[36]
Menadione	DMSJDTY	Approved	Menadione affects the expression of T-box transcription factor TBX2 (TBX2).	[37]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of T-box transcription factor TBX2 (TBX2).	[38]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of T-box transcription factor TBX2 (TBX2).	[39]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of T-box transcription factor TBX2 (TBX2).	[40]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of T-box transcription factor TBX2 (TBX2).	[42]

References

• [1] Expression Pattern of Cdkn2b and Its Regulators in Canine Mammary Tumors.Anticancer Res. 2018 Nov;38(11):6333-6338. doi: 10.21873/anticanres.12991.
• [2] TBX2 overexpression promotes proliferation and invasion through epithelial-mesenchymal transition and ERK signaling pathway.Exp Ther Med. 2019 Jan;17(1):723-729. doi: 10.3892/etm.2018.7028. Epub 2018 Nov 28.
• [3] Transcriptomic Alterations in Lung Adenocarcinoma Unveil New Mechanisms Targeted by the TBX2 Subfamily of Tumor Suppressor Genes.Front Oncol. 2018 Oct 30;8:482. doi: 10.3389/fonc.2018.00482. eCollection 2018.
• [4] Expression of TBX2 promotes anchorage-independent growth and survival in the p53-negative SW13 adrenocortical carcinoma.Cancer Lett. 2009 Jun 18;278(2):230-240. doi: 10.1016/j.canlet.2009.01.006. Epub 2009 Feb 11.
• [5] Transcriptional repression of the ectodomain sheddase ADAM10 by TBX2 and potential implication for Alzheimer's disease.Cell Mol Life Sci. 2019 Mar;76(5):1005-1025. doi: 10.1007/s00018-018-2998-2. Epub 2019 Jan 1.
• [6] Stratification based on methylation of TBX2 and TBX3 into three molecular grades predicts progression in patients with pTa-bladder cancer.Mod Pathol. 2015 Apr;28(4):515-22. doi: 10.1038/modpathol.2014.145. Epub 2014 Nov 14.
• [7] Tbx2 represses expression of Connexin43 in osteoblastic-like cells.Calcif Tissue Int. 2004 Jun;74(6):561-73. doi: 10.1007/s00223-003-0106-5.
• [8] Prognostic significance of high metabolic activity in breast cancer: PET signature in breast cancer.Biochem Biophys Res Commun. 2019 Mar 26;511(1):185-191. doi: 10.1016/j.bbrc.2019.02.035. Epub 2019 Feb 15.
• [9] TBX2 represses CST6 resulting in uncontrolled legumain activity to sustain breast cancer proliferation: a novel cancer-selective target pathway with therapeutic opportunities.Oncotarget. 2014 Mar 30;5(6):1609-20. doi: 10.18632/oncotarget.1707.
• [10] The T-box transcription factors TBX2 and TBX3 in mammary gland development and breast cancer.J Mammary Gland Biol Neoplasia. 2013 Jun;18(2):143-7. doi: 10.1007/s10911-013-9282-8. Epub 2013 Apr 28.
• [11] Morphogenetic defects underlie Superior Coloboma, a newly identified closure disorder of the dorsal eye.PLoS Genet. 2018 Mar 9;14(3):e1007246. doi: 10.1371/journal.pgen.1007246. eCollection 2018 Mar.
• [12] Increased expression of TBX2 is a novel independent prognostic biomarker of a worse outcome in colorectal cancer patients after curative surgery and a potential therapeutic target.Med Oncol. 2013 Dec;30(4):688. doi: 10.1007/s12032-013-0688-3. Epub 2013 Aug 20.
• [13] Expression of T-box transcription factors 2, 4 and 5 is decreased in the branching airway mesenchyme of nitrofen-induced hypoplastic lungs.Pediatr Surg Int. 2017 Feb;33(2):139-143. doi: 10.1007/s00383-016-4005-z. Epub 2016 Nov 11.
• [14] Bone Metastasis of Prostate Cancer Can Be Therapeutically Targeted at the TBX2-WNT Signaling Axis.Cancer Res. 2017 Mar 15;77(6):1331-1344. doi: 10.1158/0008-5472.CAN-16-0497. Epub 2017 Jan 20.
• [15] High TBX2 expression predicts poor prognosis in non-small cell lung cancer.Neoplasma. 2014;61(4):476-80.
• [16] TBX2 expression is associated with platinum-sensitivity of ovarian serous carcinoma.Oncol Lett. 2018 Mar;15(3):3085-3090. doi: 10.3892/ol.2017.7719. Epub 2017 Dec 29.
• [17] Expression and clinical significance of tbx2 in pancreatic cancer.Asian Pac J Cancer Prev. 2009 Jan-Mar;10(1):118-22.
• [18] Genome-wide analysis of CpG island methylation in bladder cancer identified TBX2, TBX3, GATA2, and ZIC4 as pTa-specific prognostic markers.Eur Urol. 2012 Jun;61(6):1245-56. doi: 10.1016/j.eururo.2012.01.011. Epub 2012 Jan 18.
• [19] TBX3 represses TBX2 under the control of the PRC2 complex in skeletal muscle and rhabdomyosarcoma.Oncogenesis. 2019 Apr 12;8(4):27. doi: 10.1038/s41389-019-0137-z.
• [20] Novel and functional sequence variants within the TBX2 gene promoter in ventricular septal defects.Biochimie. 2013 Sep;95(9):1807-9. doi: 10.1016/j.biochi.2013.05.007. Epub 2013 May 28.
• [21] Microdeletion of 17q22q23.2 encompassing TBX2 and TBX4 in a patient with congenital microcephaly, thyroid duct cyst, sensorineural hearing loss, and pulmonary hypertension. Am J Med Genet A. 2011 Feb;155A(2):418-23. doi: 10.1002/ajmg.a.33827. Epub 2011 Jan 13.
• [22] Plasma DNA methylation marker and hepatocellular carcinoma risk prediction model for the general population.Carcinogenesis. 2017 Oct 1;38(10):1021-1028. doi: 10.1093/carcin/bgx078.
• [23] Interethnic analyses of blood pressure loci in populations of East Asian and European descent.Nat Commun. 2018 Nov 28;9(1):5052. doi: 10.1038/s41467-018-07345-0.
• [24] TBX2 expression is regulated by PAX3 in the melanocyte lineage.Pigment Cell Melanoma Res. 2013 Jan;26(1):67-77. doi: 10.1111/pcmr.12029. Epub 2012 Nov 21.
• [25] The role of Tbx2 and Tbx3 in mammary development and tumorigenesis.J Mammary Gland Biol Neoplasia. 2004 Apr;9(2):109-18. doi: 10.1023/B:JOMG.0000037156.64331.3f.
• [26] Tbx2 confers poor prognosis in glioblastoma and promotes temozolomide resistance with change of mitochondrial dynamics.Onco Targets Ther. 2017 Feb 20;10:1059-1069. doi: 10.2147/OTT.S124012. eCollection 2017.
• [27] Fetal Arrhythmias: Genetic Background and Clinical Implications.Pediatr Cardiol. 2019 Feb;40(2):247-256. doi: 10.1007/s00246-018-2008-3. Epub 2018 Nov 26.
• [28] A regulatory variant in TBX2 promoter is related to the decreased susceptibility of congenital heart disease in the Han Chinese population.Mol Genet Genomic Med. 2019 Feb;7(2):e00530. doi: 10.1002/mgg3.530. Epub 2018 Dec 7.
• [29] TBX2 over-expression promotes nasopharyngeal cancer cell proliferation and invasion.Oncotarget. 2017 Apr 13;8(32):52699-52707. doi: 10.18632/oncotarget.17084. eCollection 2017 Aug 8.
• [30] 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.
• [31] Evaluation of a human iPSC-derived BBB model for repeated dose toxicity testing with cyclosporine A as model compound. Toxicol In Vitro. 2021 Jun;73:105112. doi: 10.1016/j.tiv.2021.105112. Epub 2021 Feb 22.
• [32] 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.
• [33] 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.
• [34] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [35] 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.
• [36] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [37] 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.
• [38] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [39] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [40] 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.
• [41] 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.
• [42] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.