Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7RZRVK)

• DOT Name: TOX high mobility group box family member 2 (TOX2)
• Synonyms: Granulosa cell HMG box protein 1; GCX-1
• Gene Name: TOX2
• Related Disease:
  Advanced cancer
  Chronic obstructive pulmonary disease
  Colon cancer
  Colorectal adenocarcinoma
  Colorectal adenoma
  Colorectal cancer
  Colorectal cancer, susceptibility to, 1
  Colorectal cancer, susceptibility to, 10
  Colorectal cancer, susceptibility to, 12
  Colorectal carcinoma
  Colorectal neoplasm
  Lung neoplasm
  Major depressive disorder
  Neoplasm
• UniProt ID: TOX2_HUMAN
• Pfam ID: PF00505
• Sequence:
  MQQTRTEAVAGAFSRCLGFCGMRLGLLLLARHWCIAGVFPQKFDGDSAYVGMSDGNPELL
  STSQTYNGQSENNEDYEIPPITPPNLPEPSLLHLGDHEASYHSLCHGLTPNGLLPAYSYQ
  AMDLPAIMVSNMLAQDSHLLSGQLPTIQEMVHSEVAAYDSGRPGPLLGRPAMLASHMSAL
  SQSQLISQMGIRSSIAHSSPSPPGSKSATPSPSSSTQEEESEVHFKISGEKRPSADPGKK
  AKNPKKKKKKDPNEPQKPVSAYALFFRDTQAAIKGQNPSATFGDVSKIVASMWDSLGEEQ
  KQSSPDQGETKSTQANPPAKMLPPKQPMYAMPGLASFLTPSDLQAFRSGASPASLARTLG
  SKSLLPGLSASPPPPPSFPLSPTLHQQLSLPPHAQGALLSPPVSMSPAPQPPVLPTPMAL
  QVQLAMSPSPPGPQDFPHISEFPSSSGSCSPGPSNPTSSGDWDSSYPSGECGISTCSLLP
  RDKSLYLT
• Function: Putative transcriptional activator involved in the hypothalamo-pituitary-gonadal system.

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Posttranslational Modification	[1]
Chronic obstructive pulmonary disease	DISQCIRF	Strong	Genetic Variation	[2]
Colon cancer	DISVC52G	Strong	Genetic Variation	[3]
Colorectal adenocarcinoma	DISPQOUB	Strong	Genetic Variation	[3]
Colorectal adenoma	DISTSVHM	Strong	Genetic Variation	[3]
Colorectal cancer	DISNH7P9	Strong	Genetic Variation	[3]
Colorectal cancer, susceptibility to, 1	DISZ794C	Strong	Genetic Variation	[3]
Colorectal cancer, susceptibility to, 10	DISQXMYM	Strong	Genetic Variation	[3]
Colorectal cancer, susceptibility to, 12	DIS4FXJX	Strong	Genetic Variation	[3]
Colorectal carcinoma	DIS5PYL0	Strong	Genetic Variation	[3]
Colorectal neoplasm	DISR1UCN	Strong	Genetic Variation	[3]
Lung neoplasm	DISVARNB	Strong	Altered Expression	[1]
Major depressive disorder	DIS4CL3X	Strong	Altered Expression	[4]
Neoplasm	DISZKGEW	Strong	Biomarker	[1]

12 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 TOX high mobility group box family member 2 (TOX2).	[5]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of TOX high mobility group box family member 2 (TOX2).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of TOX high mobility group box family member 2 (TOX2).	[7]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of TOX high mobility group box family member 2 (TOX2).	[9]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of TOX high mobility group box family member 2 (TOX2).	[10]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of TOX high mobility group box family member 2 (TOX2).	[11]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of TOX high mobility group box family member 2 (TOX2).	[12]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of TOX high mobility group box family member 2 (TOX2).	[13]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of TOX high mobility group box family member 2 (TOX2).	[12]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of TOX high mobility group box family member 2 (TOX2).	[16]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of TOX high mobility group box family member 2 (TOX2).	[17]
CH-223191	DMMJZYC	Investigative	CH-223191 increases the expression of TOX high mobility group box family member 2 (TOX2).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of TOX high mobility group box family member 2 (TOX2).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of TOX high mobility group box family member 2 (TOX2).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of TOX high mobility group box family member 2 (TOX2).	[15]

References

• [1] 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.
• [2] A genome-wide association study identifies risk loci for spirometric measures among smokers of European and African ancestry.BMC Genet. 2015 Dec 3;16:138. doi: 10.1186/s12863-015-0299-4.
• [3] Discovery of common and rare genetic risk variants for colorectal cancer.Nat Genet. 2019 Jan;51(1):76-87. doi: 10.1038/s41588-018-0286-6. Epub 2018 Dec 3.
• [4] Genome-wide Regional Heritability Mapping Identifies a Locus Within the TOX2 Gene Associated With Major Depressive Disorder.Biol Psychiatry. 2017 Sep 1;82(5):312-321. doi: 10.1016/j.biopsych.2016.12.012. Epub 2016 Dec 16.
• [5] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [6] 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.
• [7] The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
• [8] 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.
• [9] 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.
• [10] 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.
• [11] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [12] 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.
• [13] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.
• [18] Adaptive changes in global gene expression profile of lung carcinoma A549 cells acutely exposed to distinct types of AhR ligands. Toxicol Lett. 2018 Aug;292:162-174.