Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTRGSGH9)

• DOT Name: Homeobox protein OTX1 (OTX1)
• Synonyms: Orthodenticle homolog 1
• Gene Name: OTX1
• Related Disease:
  Adenocarcinoma
  Autism
  Autism spectrum disorder
  Bladder cancer
  Breast cancer
  Breast carcinoma
  Hepatocellular carcinoma
  Neoplasm
  Pervasive developmental disorder
  Urinary bladder cancer
  Urinary bladder neoplasm
  Carcinoma
  Clear cell renal carcinoma
  Gastric cancer
  Medulloblastoma
  Squamous cell carcinoma
  Stomach cancer
  Epilepsy
  Advanced cancer
  Colorectal carcinoma
  Proliferative vitreoretinopathy
• UniProt ID: OTX1_HUMAN
• Pfam ID: PF00046 ; PF03529
• Sequence:
  MMSYLKQPPYGMNGLGLAGPAMDLLHPSVGYPATPRKQRRERTTFTRSQLDVLEALFAKT
  RYPDIFMREEVALKINLPESRVQVWFKNRRAKCRQQQQSGSGTKSRPAKKKSSPVRESSG
  SESSGQFTPPAVSSSASSSSSASSSSANPAAAAAAGLGGNPVAAASSLSTPAASSIWSPA
  SISPGSAPASVSVPEPLAAPSNTSCMQRSVAAGAATAAASYPMSYGQGGSYGQGYPTPSS
  SYFGGVDCSSYLAPMHSHHHPHQLSPMAPSSMAGHHHHHPHAHHPLSQSSGHHHHHHHHH
  HQGYGGSGLAFNSADCLDYKEPGAAAASSAWKLNFNSPDCLDYKDQASWRFQVL
• Function: Probably plays a role in the development of the brain and the sense organs. Can bind to the BCD target sequence (BTS): 5'-TCTAATCCC-3'.
• Tissue Specificity: Expressed in brain. Detected in the anterior part of the neural fetal retina (at protein level).
• KEGG Pathway: Sig.ling pathways regulating pluripotency of stem cells (hsa04550)

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adenocarcinoma	DIS3IHTY	Strong	Altered Expression	[1]
Autism	DISV4V1Z	Strong	Genetic Variation	[2]
Autism spectrum disorder	DISXK8NV	Strong	Genetic Variation	[2]
Bladder cancer	DISUHNM0	Strong	Biomarker	[3]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[4]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[4]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[5]
Neoplasm	DISZKGEW	Strong	Biomarker	[1]
Pervasive developmental disorder	DIS51975	Strong	Biomarker	[2]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[3]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[3]
Carcinoma	DISH9F1N	moderate	Biomarker	[6]
Clear cell renal carcinoma	DISBXRFJ	moderate	Biomarker	[7]
Gastric cancer	DISXGOUK	moderate	Biomarker	[8]
Medulloblastoma	DISZD2ZL	moderate	Biomarker	[9]
Squamous cell carcinoma	DISQVIFL	moderate	Biomarker	[10]
Stomach cancer	DISKIJSX	moderate	Biomarker	[8]
Epilepsy	DISBB28L	Disputed	Biomarker	[11]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[12]
Colorectal carcinoma	DIS5PYL0	Limited	Biomarker	[13]
Proliferative vitreoretinopathy	DISZTEK1	Limited	Altered Expression	[14]

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 Homeobox protein OTX1 (OTX1).	[15]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Homeobox protein OTX1 (OTX1).	[16]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Homeobox protein OTX1 (OTX1).	[17]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Homeobox protein OTX1 (OTX1).	[19]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Homeobox protein OTX1 (OTX1).	[21]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Homeobox protein OTX1 (OTX1).	[22]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Homeobox protein OTX1 (OTX1).	[23]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Homeobox protein OTX1 (OTX1).	[24]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID increases the expression of Homeobox protein OTX1 (OTX1).	[25]

2 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 Homeobox protein OTX1 (OTX1).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Homeobox protein OTX1 (OTX1).	[20]

References

• [1] Identification of OTX1 and OTX2 As Two Possible Molecular Markers for Sinonasal Carcinomas and Olfactory Neuroblastomas.J Vis Exp. 2019 Feb 28;(144). doi: 10.3791/56880.
• [2] 2p15-p16.1 microdeletion syndrome: molecular characterization and association of the OTX1 and XPO1 genes with autism spectrum disorders.Eur J Hum Genet. 2011 Dec;19(12):1264-70. doi: 10.1038/ejhg.2011.112. Epub 2011 Jul 13.
• [3] FGFR3, TERT and OTX1 as a Urinary Biomarker Combination for Surveillance of Patients with Bladder Cancer in a Large Prospective Multicenter Study.J Urol. 2017 Jun;197(6):1410-1418. doi: 10.1016/j.juro.2016.12.096. Epub 2016 Dec 31.
• [4] OTX1 expression in breast cancer is regulated by p53.Oncogene. 2011 Jul 7;30(27):3096-103. doi: 10.1038/onc.2011.31. Epub 2011 Apr 11.
• [5] OTX1 Contributes to Hepatocellular Carcinoma Progression by Regulation of ERK/MAPK Pathway.J Korean Med Sci. 2016 Aug;31(8):1215-23. doi: 10.3346/jkms.2016.31.8.1215. Epub 2016 Jun 3.
• [6] OTX1 and OTX2 as possible molecular markers of sinonasal carcinomas and olfactory neuroblastomas.Eur J Histochem. 2017 Feb 9;61(1):2730. doi: 10.4081/ejh.2017.2730.
• [7] Identification of a 5-Gene Signature Predicting Progression and Prognosis of Clear Cell Renal Cell Carcinoma.Med Sci Monit. 2019 Jun 13;25:4401-4413. doi: 10.12659/MSM.917399.
• [8] Dowregulation of OTX1 attenuates gastric cancer cell proliferation, migration and invasion.Oncol Rep. 2018 Oct;40(4):1907-1916. doi: 10.3892/or.2018.6596. Epub 2018 Jul 24.
• [9] OTX1 and OTX2 Genes in Medulloblastoma.World Neurosurg. 2019 Jul;127:e58-e64. doi: 10.1016/j.wneu.2019.02.013. Epub 2019 Feb 21.
• [10] DNA methylation biomarkers for lung cancer.Tumour Biol. 2012 Apr;33(2):287-96. doi: 10.1007/s13277-011-0282-2. Epub 2011 Dec 6.
• [11] Developmental lineage of cell types in cortical dysplasia with balloon cells.Brain. 2007 Sep;130(Pt 9):2267-76. doi: 10.1093/brain/awm175.
• [12] In-depth characterization of the salivary adenoid cystic carcinoma transcriptome with emphasis on dominant cell type.Cancer. 2016 May 15;122(10):1513-22. doi: 10.1002/cncr.29959. Epub 2016 Mar 8.
• [13] The lncRNA FEZF1-AS1 Promotes the Progression of Colorectal Cancer Through Regulating OTX1 and Targeting miR-30a-5p.Oncol Res. 2020 Feb 7;28(1):51-63. doi: 10.3727/096504019X15619783964700. Epub 2019 Jul 3.
• [14] Expression of VEGF-A, Otx homeobox and p53 family genes in proliferative vitreoretinopathy.Mediators Inflamm. 2013;2013:857380. doi: 10.1155/2013/857380. Epub 2013 Oct 21.
• [15] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [16] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [17] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [18] 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.
• [19] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [20] 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.
• [21] Loss of TRIM33 causes resistance to BET bromodomain inhibitors through MYC- and TGF-beta-dependent mechanisms. Proc Natl Acad Sci U S A. 2016 Aug 2;113(31):E4558-66.
• [22] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [23] 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.
• [24] Cellular reactions to long-term volatile organic compound (VOC) exposures. Sci Rep. 2016 Dec 1;6:37842. doi: 10.1038/srep37842.
• [25] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.