Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTE8BL5Z)

• DOT Name: Thymocyte selection-associated high mobility group box protein TOX (TOX)
• Synonyms: Thymus high mobility group box protein TOX
• Gene Name: TOX
• Related Disease:
  Gastric cancer
  Hepatocellular carcinoma
  leukaemia
  Leukemia
  Stomach cancer
  T-cell acute lymphoblastic leukaemia
  Adenoma
  Adult T-cell leukemia/lymphoma
  Advanced cancer
  Atopic dermatitis
  Autoimmune disease
  Breast cancer
  Breast carcinoma
  Carcinoma
  Central nervous system lymphoma
  Hepatitis C virus infection
  Lung cancer
  Lung carcinoma
  Mycosis fungoides
  Primary cutaneous lymphoma
  Primary cutaneous T-cell lymphoma
  Refractive error
  Schizophrenia
  Sezary syndrome
  Skin disease
  Colorectal carcinoma
  High blood pressure
  Pulmonary tuberculosis
  Neoplasm
  Non-insulin dependent diabetes
  Pharynx neoplasm
• UniProt ID: TOX_HUMAN
• Pfam ID: PF00505
• Sequence:
  MDVRFYPPPAQPAAAPDAPCLGPSPCLDPYYCNKFDGENMYMSMTEPSQDYVPASQSYPG
  PSLESEDFNIPPITPPSLPDHSLVHLNEVESGYHSLCHPMNHNGLLPFHPQNMDLPEITV
  SNMLGQDGTLLSNSISVMPDIRNPEGTQYSSHPQMAAMRPRGQPADIRQQPGMMPHGQLT
  TINQSQLSAQLGLNMGGSNVPHNSPSPPGSKSATPSPSSSVHEDEGDDTSKINGGEKRPA
  SDMGKKPKTPKKKKKKDPNEPQKPVSAYALFFRDTQAAIKGQNPNATFGEVSKIVASMWD
  GLGEEQKQVYKKKTEAAKKEYLKQLAAYRASLVSKSYSEPVDVKTSQPPQLINSKPSVFH
  GPSQAHSALYLSSHYHQQPGMNPHLTAMHPSLPRNIAPKPNNQMPVTVSIANMAVSPPPP
  LQISPPLHQHLNMQQHQPLTMQQPLGNQLPMQVQSALHSPTMQQGFTLQPDYQTIINPTS
  TAAQVVTQAMEYVRSGCRNPPPQPVDWNNDYCSSGGMQRDKALYLT
• Function: Transcriptional regulator with a major role in neural stem cell commitment and corticogenesis as well as in lymphoid cell development and lymphoid tissue organogenesis. Binds to GC-rich DNA sequences in the proximity of transcription start sites and may alter chromatin structure, modifying access of transcription factors to DNA. During cortical development, controls the neural stem cell pool by inhibiting the switch from proliferative to differentiating progenitors. Beyond progenitor cells, promotes neurite outgrowth in newborn neurons migrating to reach the cortical plate. May activate or repress critical genes for neural stem cell fate such as SOX2, EOMES and ROBO2. Plays an essential role in the development of lymphoid tissue-inducer (LTi) cells, a subset necessary for the formation of secondary lymphoid organs: peripheral lymph nodes and Peyer's patches. Acts as a developmental checkpoint and regulates thymocyte positive selection toward T cell lineage commitment. Required for the development of various T cell subsets, including CD4-positive helper T cells, CD8-positive cytotoxic T cells, regulatory T cells and CD1D-dependent natural killer T (NKT) cells. Required for the differentiation of common lymphoid progenitors (CMP) to innate lymphoid cells (ILC). May regulate the NOTCH-mediated gene program, promoting differentiation of the ILC lineage. Required at the progenitor phase of NK cell development in the bone marrow to specify NK cell lineage commitment. Upon chronic antigen stimulation, diverts T cell development by promoting the generation of exhaustive T cells, while suppressing effector and memory T cell programming. May regulate the expression of genes encoding inhibitory receptors such as PDCD1 and induce the exhaustion program, to prevent the overstimulation of T cells and activation-induced cell death.
• Tissue Specificity: Expressed in NK cells . Highly expressed in tumor-infiltrating CD8-positive T cells (at protein level) .

Molecular Interaction Atlas (MIA) of This DOT

31 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Gastric cancer	DISXGOUK	Definitive	Altered Expression	[1]
Hepatocellular carcinoma	DIS0J828	Definitive	Altered Expression	[2]
leukaemia	DISS7D1V	Definitive	Biomarker	[3]
Leukemia	DISNAKFL	Definitive	Biomarker	[3]
Stomach cancer	DISKIJSX	Definitive	Altered Expression	[1]
T-cell acute lymphoblastic leukaemia	DIS17AI2	Definitive	Biomarker	[3]
Adenoma	DIS78ZEV	Strong	Altered Expression	[4]
Adult T-cell leukemia/lymphoma	DIS882XU	Strong	Biomarker	[5]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Atopic dermatitis	DISTCP41	Strong	Biomarker	[6]
Autoimmune disease	DISORMTM	Strong	Altered Expression	[7]
Breast cancer	DIS7DPX1	Strong	Posttranslational Modification	[8]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[9]
Carcinoma	DISH9F1N	Strong	Altered Expression	[4]
Central nervous system lymphoma	DISBYQTA	Strong	Posttranslational Modification	[10]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[11]
Lung cancer	DISCM4YA	Strong	Altered Expression	[12]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[12]
Mycosis fungoides	DIS62RB8	Strong	Altered Expression	[13]
Primary cutaneous lymphoma	DISY0E8H	Strong	Altered Expression	[6]
Primary cutaneous T-cell lymphoma	DIS35WVW	Strong	Biomarker	[14]
Refractive error	DISWNEQ1	Strong	Genetic Variation	[15]
Schizophrenia	DISSRV2N	Strong	Biomarker	[16]
Sezary syndrome	DISFMTC7	Strong	Altered Expression	[13]
Skin disease	DISDW8R6	Strong	Altered Expression	[17]
Colorectal carcinoma	DIS5PYL0	moderate	Biomarker	[18]
High blood pressure	DISY2OHH	moderate	Genetic Variation	[19]
Pulmonary tuberculosis	DIS6FLUM	moderate	Genetic Variation	[20]
Neoplasm	DISZKGEW	Limited	Biomarker	[1]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Biomarker	[21]
Pharynx neoplasm	DISQCA3F	Limited	Biomarker	[22]

12 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 Thymocyte selection-associated high mobility group box protein TOX (TOX).	[23]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Thymocyte selection-associated high mobility group box protein TOX (TOX).	[24]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Thymocyte selection-associated high mobility group box protein TOX (TOX).	[25]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Thymocyte selection-associated high mobility group box protein TOX (TOX).	[26]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Thymocyte selection-associated high mobility group box protein TOX (TOX).	[27]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Thymocyte selection-associated high mobility group box protein TOX (TOX).	[27]
Melphalan	DMOLNHF	Approved	Melphalan decreases the expression of Thymocyte selection-associated high mobility group box protein TOX (TOX).	[28]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Thymocyte selection-associated high mobility group box protein TOX (TOX).	[27]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Thymocyte selection-associated high mobility group box protein TOX (TOX).	[29]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Thymocyte selection-associated high mobility group box protein TOX (TOX).	[30]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Thymocyte selection-associated high mobility group box protein TOX (TOX).	[32]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Thymocyte selection-associated high mobility group box protein TOX (TOX).	[33]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Thymocyte selection-associated high mobility group box protein TOX (TOX).	[31]

References

• [1] Sanguinarine inhibits the tumorigenesis of gastric cancer by regulating the TOX/DNA-PKcs/ KU70/80 pathway.Pathol Res Pract. 2019 Nov;215(11):152677. doi: 10.1016/j.prp.2019.152677. Epub 2019 Sep 27.
• [2] TOX promotes the exhaustion of antitumor CD8(+) T cells by preventing PD1 degradation in hepatocellular carcinoma.J Hepatol. 2019 Oct;71(4):731-741. doi: 10.1016/j.jhep.2019.05.015. Epub 2019 Jun 5.
• [3] TOX Regulates Growth, DNA Repair, and Genomic Instability in T-cell Acute Lymphoblastic Leukemia.Cancer Discov. 2017 Nov;7(11):1336-1353. doi: 10.1158/2159-8290.CD-17-0267. Epub 2017 Oct 3.
• [4] TOX expression decreases with progression of colorectal cancers and is associated with CD4 T-cell density and Fusobacterium nucleatum infection.Hum Pathol. 2018 Sep;79:93-101. doi: 10.1016/j.humpath.2018.05.008. Epub 2018 May 21.
• [5] An Index Case of Concomitant Tumoral and Ichthyosiform Mycosis Fungoides-Like Presentation of Chronic Adult T-cell Leukemia/Lymphoma Associated With Upregulation of TOX.Am J Dermatopathol. 2017 Jan;39(1):28-32. doi: 10.1097/DAD.0000000000000537.
• [6] TOX expression in different subtypes of cutaneous lymphoma.Arch Dermatol Res. 2014 Nov;306(9):843-9. doi: 10.1007/s00403-014-1501-7. Epub 2014 Sep 13.
• [7] Expression of the DNA-Binding Factor TOX Promotes the Encephalitogenic Potential of Microbe-Induced Autoreactive CD8(+) T Cells.Immunity. 2018 May 15;48(5):937-950.e8. doi: 10.1016/j.immuni.2018.04.005.
• [8] Differential epigenetic regulation of TOX subfamily high mobility group box genes in lung and breast cancers.PLoS One. 2012;7(4):e34850. doi: 10.1371/journal.pone.0034850. Epub 2012 Apr 4.
• [9] Identification of novel tumor markers in prostate, colon and breast cancer by unbiased methylation profiling.PLoS One. 2008 Apr 30;3(4):e2079. doi: 10.1371/journal.pone.0002079.
• [10] Genome-Wide Analysis Uncovers Novel Recurrent Alterations in Primary Central Nervous System Lymphomas.Clin Cancer Res. 2015 Sep 1;21(17):3986-94. doi: 10.1158/1078-0432.CCR-14-2116. Epub 2015 May 19.
• [11] TOX reinforces the phenotype and longevity of exhausted T cells in chronic viral infection.Nature. 2019 Jul;571(7764):265-269. doi: 10.1038/s41586-019-1326-9. Epub 2019 Jun 17.
• [12] TOX3 is a favorable prognostic indicator and potential immunomodulatory factor in lung adenocarcinoma.Oncol Lett. 2019 Oct;18(4):4144-4152. doi: 10.3892/ol.2019.10748. Epub 2019 Aug 16.
• [13] Molecular profiling of TOX-deficient neoplastic cells in cutaneous T cell lymphoma.Arch Dermatol Res. 2020 Sep;312(7):513-525. doi: 10.1007/s00403-019-02000-0. Epub 2019 Nov 1.
• [14] miRNA?35a regulates Hut78 cell proliferation via the GATA?/TOX signaling pathway.Mol Med Rep. 2019 Mar;19(3):2361-2367. doi: 10.3892/mmr.2019.9885. Epub 2019 Jan 22.
• [15] Genome-wide association study for refractive astigmatism reveals genetic co-determination with spherical equivalent refractive error: the CREAM consortium.Hum Genet. 2015 Feb;134(2):131-46. doi: 10.1007/s00439-014-1500-y. Epub 2014 Nov 4.
• [16] Time dependent expression of the blood biomarkers EIF2D and TOX in patients with schizophrenia.Brain Behav Immun. 2019 Aug;80:909-915. doi: 10.1016/j.bbi.2019.05.015. Epub 2019 May 9.
• [17] Evidence of an oncogenic role of aberrant TOX activation in cutaneous T-cell lymphoma.Blood. 2015 Feb 26;125(9):1435-43. doi: 10.1182/blood-2014-05-571778. Epub 2014 Dec 29.
• [18] VEGF-A drives TOX-dependent T cell exhaustion in anti-PD-1-resistant microsatellite stable colorectal cancers.Sci Immunol. 2019 Nov 8;4(41):eaay0555. doi: 10.1126/sciimmunol.aay0555.
• [19] Intracranial aneurysm risk factor genes: relationship with intracranial aneurysm risk in a Chinese Han population.Genet Mol Res. 2015 Jun 18;14(2):6865-78. doi: 10.4238/2015.June.18.30.
• [20] Age-dependent association between pulmonary tuberculosis and common TOX variants in the 8q12-13 linkage region.Am J Hum Genet. 2013 Mar 7;92(3):407-14. doi: 10.1016/j.ajhg.2013.01.013. Epub 2013 Feb 14.
• [21] TOX and CDKN2A/B Gene Polymorphisms Are Associated with Type 2 Diabetes in Han Chinese.Sci Rep. 2015 Jul 3;5:11900. doi: 10.1038/srep11900.
• [22] Retrospective diagnosis of diphtheria by detection of the Corynebacterium diphtheriae tox gene in a formaldehyde-fixed throat swab using PCR and sequencing analysis.J Clin Microbiol. 2000 Jun;38(6):2400-2. doi: 10.1128/JCM.38.6.2400-2402.2000.
• [23] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [24] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [25] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [26] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [27] 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.
• [28] Bone marrow osteoblast damage by chemotherapeutic agents. PLoS One. 2012;7(2):e30758. doi: 10.1371/journal.pone.0030758. Epub 2012 Feb 17.
• [29] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [30] 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.
• [31] Expression and DNA methylation changes in human breast epithelial cells after bisphenol A exposure. Int J Oncol. 2012 Jul;41(1):369-77.
• [32] 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.
• [33] 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.