Details of Drug Off-Target (DOT)

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

• DOT Name: POU domain, class 2, transcription factor 3 (POU2F3)
• Synonyms: Octamer-binding protein 11; Oct-11; Octamer-binding transcription factor 11; OTF-11; Transcription factor PLA-1; Transcription factor Skn-1
• Gene Name: POU2F3
• Related Disease:
  Acute coronary syndrome
  Acute myocardial infarction
  Advanced cancer
  Alzheimer disease
  Arrhythmia
  Arteriosclerosis
  Atherosclerosis
  Breast cancer
  Breast carcinoma
  Cardiovascular disease
  Cervical cancer
  Cervical carcinoma
  Chronic renal failure
  Coronary heart disease
  Diabetic kidney disease
  Diabetic retinopathy
  End-stage renal disease
  Glanzmann thrombasthenia
  Hereditary spastic paraplegia 54
  Herpes simplex infection
  Intrahepatic cholestasis of pregnancy
  Optic neuritis
  Small-cell lung cancer
  Vascular disease
  Vascular purpura
  Ventricular tachycardia
  Von willebrand disease
  Bacterial infection
  Neoplasm
  Coxopodopatellar syndrome
• UniProt ID: PO2F3_HUMAN
• Pfam ID: PF00046 ; PF00157
• Sequence:
  MVNLESMHTDIKMSGDVADSTDARSTLSQVEPGNDRNGLDFNRQIKTEDLSDSLQQTLSH
  RPCHLSQGPAMMSGNQMSGLNASPCQDMASLHPLQQLVLVPGHLQSVSQFLLSQTQPGQQ
  GLQPNLLPFPQQQSGLLLPQTGPGLASQAFGHPGLPGSSLEPHLEASQHLPVPKHLPSSG
  GADEPSDLEELEKFAKTFKQRRIKLGFTQGDVGLAMGKLYGNDFSQTTISRFEALNLSFK
  NMCKLKPLLEKWLNDAESSPSDPSVSTPSSYPSLSEVFGRKRKKRTSIETNIRLTLEKRF
  QDNPKPSSEEISMIAEQLSMEKEVVRVWFCNRRQKEKRINCPVATPIKPPVYNSRLVSPS
  GSLGPLSVPPVHSTMPGTVTSSCSPGNNSRPSSPGSGLHASSPTASQNNSKAAVNSASSF
  NSSGSWYRWNHSTYLH
• Function: Transcription factor that binds to the octamer motif (5'-ATTTGCAT-3') and regulates cell type-specific differentiation pathways. Involved in the regulation of keratinocytes differentiation. The POU2F3-POU2AF2/POU2AF3 complex drives the expression of tuft-cell-specific genes, a rare chemosensory cells that coordinate immune and neural functions within mucosal epithelial tissues.
• Tissue Specificity: Specifically expressed in epidermis and cultured keratinocytes.
• KEGG Pathway:
  Herpes simplex virus 1 infection (hsa05168)
  Lipid and atherosclerosis (hsa05417)

Molecular Interaction Atlas (MIA) of This DOT

30 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute coronary syndrome	DIS7DYEW	Strong	Genetic Variation	[1]
Acute myocardial infarction	DISE3HTG	Strong	Genetic Variation	[2]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[3]
Alzheimer disease	DISF8S70	Strong	Biomarker	[4]
Arrhythmia	DISFF2NI	Strong	Genetic Variation	[5]
Arteriosclerosis	DISK5QGC	Strong	Genetic Variation	[6]
Atherosclerosis	DISMN9J3	Strong	Genetic Variation	[6]
Breast cancer	DIS7DPX1	Strong	Biomarker	[7]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[7]
Cardiovascular disease	DIS2IQDX	Strong	Genetic Variation	[8]
Cervical cancer	DISFSHPF	Strong	Posttranslational Modification	[9]
Cervical carcinoma	DIST4S00	Strong	Posttranslational Modification	[9]
Chronic renal failure	DISGG7K6	Strong	Genetic Variation	[10]
Coronary heart disease	DIS5OIP1	Strong	Genetic Variation	[11]
Diabetic kidney disease	DISJMWEY	Strong	Genetic Variation	[12]
Diabetic retinopathy	DISHGUJM	Strong	Biomarker	[13]
End-stage renal disease	DISXA7GG	Strong	Genetic Variation	[10]
Glanzmann thrombasthenia	DISFGGTG	Strong	Genetic Variation	[14]
Hereditary spastic paraplegia 54	DIS2AY6F	Strong	Genetic Variation	[15]
Herpes simplex infection	DISL1SAV	Strong	Altered Expression	[16]
Intrahepatic cholestasis of pregnancy	DISMHS5F	Strong	Biomarker	[17]
Optic neuritis	DISDYCHC	Strong	Genetic Variation	[18]
Small-cell lung cancer	DISK3LZD	Strong	Altered Expression	[19]
Vascular disease	DISVS67S	Strong	Genetic Variation	[20]
Vascular purpura	DIS6ZZMF	Strong	Genetic Variation	[15]
Ventricular tachycardia	DISIBXJ3	Strong	Genetic Variation	[5]
Von willebrand disease	DIS3TZCH	Strong	Genetic Variation	[21]
Bacterial infection	DIS5QJ9S	moderate	Biomarker	[22]
Neoplasm	DISZKGEW	moderate	Altered Expression	[3]
Coxopodopatellar syndrome	DISMJAT7	Limited	Genetic Variation	[23]

8 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 POU domain, class 2, transcription factor 3 (POU2F3).	[24]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of POU domain, class 2, transcription factor 3 (POU2F3).	[25]
Ivermectin	DMDBX5F	Approved	Ivermectin increases the expression of POU domain, class 2, transcription factor 3 (POU2F3).	[26]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of POU domain, class 2, transcription factor 3 (POU2F3).	[28]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of POU domain, class 2, transcription factor 3 (POU2F3).	[28]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of POU domain, class 2, transcription factor 3 (POU2F3).	[30]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of POU domain, class 2, transcription factor 3 (POU2F3).	[31]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID decreases the expression of POU domain, class 2, transcription factor 3 (POU2F3).	[32]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of POU domain, class 2, transcription factor 3 (POU2F3).	[27]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of POU domain, class 2, transcription factor 3 (POU2F3).	[29]

References

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• [3] POU2F3 is a master regulator of a tuft cell-like variant of small cell lung cancer.Genes Dev. 2018 Jul 1;32(13-14):915-928. doi: 10.1101/gad.314815.118. Epub 2018 Jun 26.
• [4] Endoplasmic reticulum-associated SKN-1A/Nrf1 mediates a cytoplasmic unfolded protein response and promotes longevity.Elife. 2019 Apr 11;8:e44425. doi: 10.7554/eLife.44425.
• [5] Cholinesterase inhibition reduces arrhythmias in asymptomatic Chagas disease.Cardiovasc Ther. 2017 Oct;35(5). doi: 10.1111/1755-5922.12288.
• [6] No evidence that the PLA1/PLA2 polymorphism of platelet glycoprotein IIIa is implicated in angiographically characterized coronary atherosclerosis and premature myocardial infarction.Blood Coagul Fibrinolysis. 2003 Dec;14(8):749-53. doi: 10.1097/00001721-200312000-00010.
• [7] Examination of POU homeobox gene expression in human breast cancer cells.Int J Cancer. 1999 Mar 31;81(1):104-12. doi: 10.1002/(sici)1097-0215(19990331)81:1<104::aid-ijc18>3.0.co;2-q.
• [8] Pharmacogenetics of aspirin resistance: a comprehensive systematic review.Br J Clin Pharmacol. 2008 Aug;66(2):222-32. doi: 10.1111/j.1365-2125.2008.03183.x. Epub 2008 Apr 22.
• [9] Aberrant promoter methylation and silencing of the POU2F3 gene in cervical cancer.Oncogene. 2006 Aug 31;25(39):5436-45. doi: 10.1038/sj.onc.1209530. Epub 2006 Apr 10.
• [10] Platelet GP IIIA polymorphism HPA-1 (PLA1/2) is associated with hypertension as the primary cause for end-stage renal disease in hemodialysis patients from Greece.In Vivo. 2009 Jan-Feb;23(1):177-81.
• [11] Association among PlA1/A2 gene polymorphism, laboratory aspirin resistance and clinical outcomes in patients with coronary artery disease: An updated meta-analysis.Sci Rep. 2019 Sep 11;9(1):13177. doi: 10.1038/s41598-019-49123-y.
• [12] Platelet glycoprotein IIIa PlA1/A2 polymorphism and its relationship with diabetic nephropathy in type 2 diabetic patients.Clin Nephrol. 2000 Apr;53(4):253-6.
• [13] Association of platelet glycoprotein receptor alpha2beta1 integrin and glycoprotein IIIa gene polymorphisms with diabetic retinopathy: evidence from 3007 subjects.Curr Eye Res. 2015 May;40(5):476-83. doi: 10.3109/02713683.2014.932386. Epub 2014 Jun 30.
• [14] Modulation of clinical phenotype of Glanzmann's thrombasthenia by thrombogenic mutations.Clin Chim Acta. 2009 May;403(1-2):156-8. doi: 10.1016/j.cca.2009.02.009. Epub 2009 Feb 24.
• [15] Mutations in DDHD2, encoding an intracellular phospholipase A(1), cause a recessive form of complex hereditary spastic paraplegia. Am J Hum Genet. 2012 Dec 7;91(6):1073-81. doi: 10.1016/j.ajhg.2012.10.017. Epub 2012 Nov 21.
• [16] A novel reporter system for cyclic AMP mediated gene expression in mammalian cells based on synthetic transgene expression system.Eur J Pharmacol. 2019 Jul 15;855:56-64. doi: 10.1016/j.ejphar.2019.04.037. Epub 2019 Apr 26.
• [17] Role of the placenta in serum autotaxin elevation during maternal cholestasis.Am J Physiol Gastrointest Liver Physiol. 2018 Sep 1;315(3):G399-G407. doi: 10.1152/ajpgi.00112.2018. Epub 2018 Jun 21.
• [18] PlA1/A2 polymorphism of the platelet glycoprotein receptor IIIA and risk of cranial ischemic complications in giant cell arteritis.Arthritis Rheum. 2007 Oct;56(10):3502-8. doi: 10.1002/art.22922.
• [19] Molecular subtypes of small cell lung cancer: a synthesis of human and mouse model data.Nat Rev Cancer. 2019 May;19(5):289-297. doi: 10.1038/s41568-019-0133-9.
• [20] Platelet glycoprotein receptor IIIa polymorphism PLA1/PLA2 and coronary risk: a meta-analysis.Thromb Haemost. 2001 Apr;85(4):626-33.
• [21] Impact of thrombogenic mutations on clinical phenotypes of von Willebrand disease.Clin Appl Thromb Hemost. 2010 Jun;16(3):281-7. doi: 10.1177/1076029609351291. Epub 2009 Dec 2.
• [22] Redirection of SKN-1 abates the negative metabolic outcomes of a perceived pathogen infection.Proc Natl Acad Sci U S A. 2019 Oct 29;116(44):22322-22330. doi: 10.1073/pnas.1909666116. Epub 2019 Oct 14.
• [23] Primary thrombophilia in Mexico IX: the glycoprotein IIIa PLA1/A2 polymorphism is not associated with the sticky platelet syndrome phenotype.Clin Appl Thromb Hemost. 2013 Nov-Dec;19(6):689-92. doi: 10.1177/1076029612448418. Epub 2012 Jun 29.
• [24] Effects of lithium and valproic acid on gene expression and phenotypic markers in an NT2 neurosphere model of neural development. PLoS One. 2013;8(3):e58822.
• [25] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [26] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [27] 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.
• [28] 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.
• [29] 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.
• [30] Comparison of transcriptome expression alterations by chronic exposure to low-dose bisphenol A in different subtypes of breast cancer cells. Toxicol Appl Pharmacol. 2019 Dec 15;385:114814. doi: 10.1016/j.taap.2019.114814. Epub 2019 Nov 9.
• [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.
• [32] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.