Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTC9NR4W)

• DOT Name: TOX high mobility group box family member 3 (TOX3)
• Synonyms: CAG trinucleotide repeat-containing gene F9 protein; Trinucleotide repeat-containing gene 9 protein
• Gene Name: TOX3
• Related Disease:
  Triple negative breast cancer
  Breast carcinoma in situ
  Breast fibrocystic disease
  Clear cell renal carcinoma
  Cleft lip
  Estrogen-receptor positive breast cancer
  Gastric cancer
  Hyperlipidemia
  Isolated cleft lip
  Liver cancer
  Lung adenocarcinoma
  Lung cancer
  Lung carcinoma
  Metastatic malignant neoplasm
  Neoplasm
  Parkinson disease
  Polycystic ovarian syndrome
  Restless legs syndrome
  Stomach cancer
  Epithelial ovarian cancer
  Hereditary breast carcinoma
  Male breast carcinoma
  Ovarian cancer
  Ovarian neoplasm
  Advanced cancer
• UniProt ID: TOX3_HUMAN
• Pfam ID: PF00505
• Sequence:
  MDVRFYPAAAGDPASLDFAQCLGYYGYSKFGNNNNYMNMAEANNAFFAASEQTFHTPSLG
  DEEFEIPPITPPPESDPALGMPDVLLPFQALSDPLPSQGSEFTPQFPPQSLDLPSITISR
  NLVEQDGVLHSSGLHMDQSHTQVSQYRQDPSLIMRSIVHMTDAARSGVMPPAQLTTINQS
  QLSAQLGLNLGGASMPHTSPSPPASKSATPSPSSSINEEDADEANRAIGEKRAAPDSGKK
  PKTPKKKKKKDPNEPQKPVSAYALFFRDTQAAIKGQNPNATFGEVSKIVASMWDSLGEEQ
  KQVYKRKTEAAKKEYLKALAAYRASLVSKAAAESAEAQTIRSVQQTLASTNLTSSLLLNT
  PLSQHGTVSASPQTLQQSLPRSIAPKPLTMRLPMNQIVTSVTIAANMPSNIGAPLISSMG
  TTMVGSAPSTQVSPSVQTQQHQMQLQQQQQQQQQQMQQMQQQQLQQHQMHQQIQQQMQQQ
  HFQHHMQQHLQQQQQHLQQQINQQQLQQQLQQRLQLQQLQHMQHQSQPSPRQHSPVASQI
  TSPIPAIGSPQPASQQHQSQIQSQTQTQVLSQVSIF
• Function: Transcriptional coactivator of the p300/CBP-mediated transcription complex. Activates transactivation through cAMP response element (CRE) sites. Protects against cell death by inducing antiapoptotic and repressing pro-apoptotic transcripts. Stimulates transcription from the estrogen-responsive or BCL-2 promoters. Required for depolarization-induced transcription activation of the C-FOS promoter in neurons. Associates with chromatin to the estrogen-responsive C3 promoter region.
• Tissue Specificity: Expressed mainly in epithelial cells. Expressed in the central nervous system (CNS), in the ileum and within the brain in the frontal and occipital lobe.

Molecular Interaction Atlas (MIA) of This DOT

25 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Triple negative breast cancer	DISAMG6N	Definitive	Genetic Variation	[1]
Breast carcinoma in situ	DISRN92I	Strong	Genetic Variation	[2]
Breast fibrocystic disease	DISUM7ID	Strong	Genetic Variation	[3]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[4]
Cleft lip	DISV3XW6	Strong	Genetic Variation	[5]
Estrogen-receptor positive breast cancer	DIS1H502	Strong	Genetic Variation	[6]
Gastric cancer	DISXGOUK	Strong	Genetic Variation	[7]
Hyperlipidemia	DIS61J3S	Strong	Genetic Variation	[3]
Isolated cleft lip	DIS2O2JV	Strong	Genetic Variation	[5]
Liver cancer	DISDE4BI	Strong	Biomarker	[8]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[9]
Lung cancer	DISCM4YA	Strong	Altered Expression	[9]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[9]
Metastatic malignant neoplasm	DIS86UK6	Strong	Biomarker	[10]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[11]
Parkinson disease	DISQVHKL	Strong	Genetic Variation	[12]
Polycystic ovarian syndrome	DISZ2BNG	Strong	Altered Expression	[13]
Restless legs syndrome	DISNWY00	Strong	Genetic Variation	[14]
Stomach cancer	DISKIJSX	Strong	Genetic Variation	[7]
Epithelial ovarian cancer	DIS56MH2	moderate	Genetic Variation	[15]
Hereditary breast carcinoma	DISAEZT5	moderate	Genetic Variation	[16]
Male breast carcinoma	DISUNQ2Q	moderate	Genetic Variation	[17]
Ovarian cancer	DISZJHAP	moderate	Genetic Variation	[15]
Ovarian neoplasm	DISEAFTY	moderate	Genetic Variation	[15]
Advanced cancer	DISAT1Z9	Limited	Altered Expression	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of TOX high mobility group box family member 3 (TOX3).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of TOX high mobility group box family member 3 (TOX3).	[19]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of TOX high mobility group box family member 3 (TOX3).	[20]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of TOX high mobility group box family member 3 (TOX3).	[21]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of TOX high mobility group box family member 3 (TOX3).	[22]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of TOX high mobility group box family member 3 (TOX3).	[23]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of TOX high mobility group box family member 3 (TOX3).	[23]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of TOX high mobility group box family member 3 (TOX3).	[24]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of TOX high mobility group box family member 3 (TOX3).	[25]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of TOX high mobility group box family member 3 (TOX3).	[26]
Amphotericin B	DMTAJQE	Approved	Amphotericin B decreases the expression of TOX high mobility group box family member 3 (TOX3).	[27]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of TOX high mobility group box family member 3 (TOX3).	[28]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of TOX high mobility group box family member 3 (TOX3).	[26]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of TOX high mobility group box family member 3 (TOX3).	[29]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of TOX high mobility group box family member 3 (TOX3).	[30]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of TOX high mobility group box family member 3 (TOX3).	[31]

References

• [1] Common breast cancer susceptibility loci are associated with triple-negative breast cancer.Cancer Res. 2011 Oct 1;71(19):6240-9. doi: 10.1158/0008-5472.CAN-11-1266. Epub 2011 Aug 15.
• [2] Genetic risk variants associated with in situ breast cancer.Breast Cancer Res. 2015 Jun 13;17(1):82. doi: 10.1186/s13058-015-0596-x.
• [3] Genetic and environmental factors and serum hormones, and risk of estrogen receptor-positive breast cancer in pre- and postmenopausal Japanese women.Oncotarget. 2017 Aug 11;8(39):65759-65769. doi: 10.18632/oncotarget.20182. eCollection 2017 Sep 12.
• [4] TOX3 inhibits cancer cell migration and invasion via transcriptional regulation of SNAI1 and SNAI2 in clear cell renal cell carcinoma.Cancer Lett. 2019 May 1;449:76-86. doi: 10.1016/j.canlet.2019.02.020. Epub 2019 Feb 14.
• [5] Two novel genes TOX3 and COL21A1 in large extended Malay families with nonsyndromic cleft lip and/or palate.Mol Genet Genomic Med. 2019 May;7(5):e635. doi: 10.1002/mgg3.635. Epub 2019 Mar 28.
• [6] Genetic variants in trinucleotide repeat-containing 9 (TNRC9) are associated with risk of estrogen receptor positive breast cancer in a Chinese population.Breast Cancer Res Treat. 2010 Nov;124(1):237-41. doi: 10.1007/s10549-010-0809-z. Epub 2010 Mar 9.
• [7] A genetic polymorphism in TOX3 is associated with survival of gastric cancer in a Chinese population.PLoS One. 2013 Sep 17;8(9):e72186. doi: 10.1371/journal.pone.0072186. eCollection 2013.
• [8] Discriminating between adaptive and carcinogenic liver hypertrophy in rat studies using logistic ridge regression analysis of toxicogenomic data: The mode of action and predictive models.Toxicol Appl Pharmacol. 2017 Mar 1;318:79-87. doi: 10.1016/j.taap.2017.01.006. Epub 2017 Jan 18.
• [9] 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.
• [10] Polymorphisms of ESR1, UGT1A1, HCN1, MAP3K1 and CYP2B6 are associated with the prognosis of hormone receptor-positive early breast cancer.Oncotarget. 2017 Mar 28;8(13):20925-20938. doi: 10.18632/oncotarget.14995.
• [11] Polymorphisms in the TOX3/LOC643714 and risk of breast cancer in south China.Int J Biol Markers. 2018 Apr 1:1724600818755633. doi: 10.1177/1724600818755633. Online ahead of print.
• [12] TOX3 Variants Are Involved in Restless Legs Syndrome and Parkinson's Disease with Opposite Effects.J Mol Neurosci. 2018 Mar;64(3):341-345. doi: 10.1007/s12031-018-1031-4. Epub 2018 Feb 5.
• [13] Relationship between abnormal TOX3 gene methylation and polycystic ovarian syndrome.Eur Rev Med Pharmacol Sci. 2017 May;21(9):2034-2038.
• [14] TOX3 gene variant could be associated with painful restless legs.Sleep Med. 2020 Jan;65:4-7. doi: 10.1016/j.sleep.2019.07.003. Epub 2019 Jul 11.
• [15] Association between invasive ovarian cancer susceptibility and 11 best candidate SNPs from breast cancer genome-wide association study.Hum Mol Genet. 2009 Jun 15;18(12):2297-304. doi: 10.1093/hmg/ddp138. Epub 2009 Mar 20.
• [16] Genetic variants associated with breast cancer risk for Ashkenazi Jewish women with strong family histories but no identifiable BRCA1/2 mutation.Hum Genet. 2013 May;132(5):523-36. doi: 10.1007/s00439-013-1269-4. Epub 2013 Jan 25.
• [17] Association of low-penetrance alleles with male breast cancer risk and clinicopathological characteristics: results from a multicenter study in Italy.Breast Cancer Res Treat. 2013 Apr;138(3):861-8. doi: 10.1007/s10549-013-2459-4. Epub 2013 Mar 7.
• [18] 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.
• [19] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [20] 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.
• [21] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [22] Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells. Toxicol Appl Pharmacol. 2009 Nov 1;240(3):355-66.
• [23] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [24] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [25] 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.
• [26] 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.
• [27] Differential expression of microRNAs and their predicted targets in renal cells exposed to amphotericin B and its complex with copper (II) ions. Toxicol Mech Methods. 2017 Sep;27(7):537-543. doi: 10.1080/15376516.2017.1333554. Epub 2017 Jun 8.
• [28] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [29] 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.
• [30] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [31] 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.