Details of Drug Off-Target (DOT)

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

• DOT Name: TOX high mobility group box family member 4 (TOX4)
• Synonyms: Epidermal Langerhans cell protein LCP1
• Gene Name: TOX4
• Related Disease:
  Neoplasm
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Carcinoma
  Endometrial carcinoma
  Epithelial ovarian cancer
  Glioma
  Lung cancer
  Lung carcinoma
  Bone osteosarcoma
  Osteosarcoma
• UniProt ID: TOX4_HUMAN
• Pfam ID: PF00505
• Sequence:
  MEFPGGNDNYLTITGPSHPFLSGAETFHTPSLGDEEFEIPPISLDSDPSLAVSDVVGHFD
  DLADPSSSQDGSFSAQYGVQTLDMPVGMTHGLMEQGGGLLSGGLTMDLDHSIGTQYSANP
  PVTIDVPMTDMTSGLMGHSQLTTIDQSELSSQLGLSLGGGTILPPAQSPEDRLSTTPSPT
  SSLHEDGVEDFRRQLPSQKTVVVEAGKKQKAPKKRKKKDPNEPQKPVSAYALFFRDTQAA
  IKGQNPNATFGEVSKIVASMWDSLGEEQKQVYKRKTEAAKKEYLKALAAYKDNQECQATV
  ETVELDPAPPSQTPSPPPMATVDPASPAPASIEPPALSPSIVVNSTLSSYVANQASSGAG
  GQPNITKLIITKQMLPSSITMSQGGMVTVIPATVVTSRGLQLGQTSTATIQPSQQAQIVT
  RSVLQAAAAAAAAASMQLPPPRLQPPPLQQMPQPPTQQQVTILQQPPPLQAMQQPPPQKV
  RINLQQQPPPLQIKSVPLPTLKMQTTLVPPTVESSPERPMNNSPEAHTVEAPSPETICEM
  ITDVVPEVESPSQMDVELVSGSPVALSPQPRCVRSGCENPPIVSKDWDNEYCSNECVVKH
  CRDVFLAWVASRNSNTVVFVK
• Function: Transcription factor that modulates cell fate reprogramming from the somatic state to the pluripotent and neuronal fate. Component of the PTW/PP1 phosphatase complex, which plays a role in the control of chromatin structure and cell cycle progression during the transition from mitosis into interphase. In liver, controls the expression of hormone-regulated gluconeogenic genes such as G6PC1 and PCK1. This regulation is independent of the insulin receptor activation.
• Tissue Specificity: Expressed in liver (at protein level).

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neoplasm	DISZKGEW	Definitive	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Carcinoma	DISH9F1N	Strong	Biomarker	[4]
Endometrial carcinoma	DISXR5CY	Strong	Biomarker	[5]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[1]
Glioma	DIS5RPEH	Strong	Biomarker	[6]
Lung cancer	DISCM4YA	moderate	Altered Expression	[7]
Lung carcinoma	DISTR26C	moderate	Altered Expression	[7]
Bone osteosarcoma	DIST1004	Limited	Biomarker	[8]
Osteosarcoma	DISLQ7E2	Limited	Biomarker	[8]

9 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 TOX high mobility group box family member 4 (TOX4).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of TOX high mobility group box family member 4 (TOX4).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of TOX high mobility group box family member 4 (TOX4).	[11]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of TOX high mobility group box family member 4 (TOX4).	[12]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of TOX high mobility group box family member 4 (TOX4).	[13]
Selenium	DM25CGV	Approved	Selenium increases the expression of TOX high mobility group box family member 4 (TOX4).	[14]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of TOX high mobility group box family member 4 (TOX4).	[15]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of TOX high mobility group box family member 4 (TOX4).	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of TOX high mobility group box family member 4 (TOX4).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of TOX high mobility group box family member 4 (TOX4).	[16]

References

• [1] Migration-inducing gene 7 promotes tumorigenesis and angiogenesis and independently predicts poor prognosis of epithelial ovarian cancer.Oncotarget. 2016 May 10;7(19):27552-66. doi: 10.18632/oncotarget.8487.
• [2] 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.
• [3] Tissue-specific Co-expression of Long Non-coding and Coding RNAs Associated with Breast Cancer.Sci Rep. 2016 Sep 6;6:32731. doi: 10.1038/srep32731.
• [4] HGF and ligation of alphavbeta5 integrin induce a novel, cancer cell-specific gene expression required for cell scattering.Exp Cell Res. 2004 Jan 15;292(2):274-87. doi: 10.1016/j.yexcr.2003.09.016.
• [5] Targeting migration inducting gene-7 inhibits carcinoma cell invasion, early primary tumor growth, and stimulates monocyte oncolytic activity.Mol Cancer Ther. 2009 Aug;8(8):2412-23. doi: 10.1158/1535-7163.MCT-09-0186. Epub 2009 Aug 11.
• [6] Silencing of Mig-7 expression inhibits in-vitro invasiveness and vasculogenic mimicry of human glioma U87 Cells.Neuroreport. 2019 Dec 10;30(17):1135-1142. doi: 10.1097/WNR.0000000000001317.
• [7] Recombinant viral capsid protein VP1 suppresses lung cancer metastasis by inhibiting COX-2/PGE2 and MIG-7.Oncotarget. 2014 Jun 15;5(11):3931-43. doi: 10.18632/oncotarget.2040.
• [8] Migration-inducing gene-7 independently predicts poor prognosis of human osteosarcoma and is associated with vasculogenic mimicry.Exp Cell Res. 2018 Aug 1;369(1):80-89. doi: 10.1016/j.yexcr.2018.05.008. Epub 2018 May 8.
• [9] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [10] 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.
• [11] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [12] 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.
• [13] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [14] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [15] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [16] 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.
• [17] 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.