Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0ZN9EJ)

• DOT Name: Iroquois-class homeodomain protein IRX-1 (IRX1)
• Synonyms: Homeodomain protein IRXA1; Iroquois homeobox protein 1
• Gene Name: IRX1
• Related Disease:
  Androgen insensitivity syndrome
  Glioma
  Lung squamous cell carcinoma
  Neoplasm
  Osteoarthritis
  Rheumatoid arthritis
  Seminoma
  Squamous cell carcinoma
  Bone osteosarcoma
  Gastric cancer
  Head-neck squamous cell carcinoma
  North Carolina macular dystrophy
  Osteosarcoma
  Pulmonary disease
  Stomach cancer
• UniProt ID: IRX1_HUMAN
• Pfam ID: PF05920
• Sequence:
  MSFPQLGYPQYLSAAGPGAYGGERPGVLAAAAAAAAAASSGRPGAAELGGGAGAAAVTSV
  LGMYAAAGPYAGAPNYSAFLPYAADLSLFSQMGSQYELKDNPGVHPATFAAHTAPAYYPY
  GQFQYGDPGRPKNATRESTSTLKAWLNEHRKNPYPTKGEKIMLAIITKMTLTQVSTWFAN
  ARRRLKKENKVTWGARSKDQEDGALFGSDTEGDPEKAEDDEEIDLESIDIDKIDEHDGDQ
  SNEDDEDKAEAPHAPAAPSALARDQGSPLAAADVLKPQDSPLGLAKEAPEPGSTRLLSPG
  AAAGGLQGAPHGKPKIWSLAETATSPDGAPKASPPPPAGHPGAHGPSAGAPLQHPAFLPS
  HGLYTCHIGKFSNWTNSAFLAQGSLLNMRSFLGVGAPHAAPHGPHLPAPPPPQPPVAIAP
  GALNGDKASVRSSPTLPERDLVPRPDSPAQQLKSPFQPVRDNSLAPQEGTPRILAALPSA

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Androgen insensitivity syndrome	DISUZBBO	Strong	Altered Expression	[1]
Glioma	DIS5RPEH	Strong	Biomarker	[2]
Lung squamous cell carcinoma	DISXPIBD	Strong	Biomarker	[3]
Neoplasm	DISZKGEW	Strong	Biomarker	[4]
Osteoarthritis	DIS05URM	Strong	Biomarker	[5]
Rheumatoid arthritis	DISTSB4J	Strong	Biomarker	[6]
Seminoma	DIS3J8LJ	Strong	Biomarker	[7]
Squamous cell carcinoma	DISQVIFL	Strong	Posttranslational Modification	[8]
Bone osteosarcoma	DIST1004	moderate	Biomarker	[9]
Gastric cancer	DISXGOUK	moderate	Biomarker	[10]
Head-neck squamous cell carcinoma	DISF7P24	moderate	Biomarker	[11]
North Carolina macular dystrophy	DISMPOAO	moderate	Genetic Variation	[12]
Osteosarcoma	DISLQ7E2	moderate	Biomarker	[9]
Pulmonary disease	DIS6060I	Limited	Biomarker	[13]
Stomach cancer	DISKIJSX	Limited	Biomarker	[10]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Mitoxantrone	DMM39BF	Approved	Iroquois-class homeodomain protein IRX-1 (IRX1) affects the response to substance of Mitoxantrone.	[23]

2 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 Iroquois-class homeodomain protein IRX-1 (IRX1).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Iroquois-class homeodomain protein IRX-1 (IRX1).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Iroquois-class homeodomain protein IRX-1 (IRX1).	[15]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Iroquois-class homeodomain protein IRX-1 (IRX1).	[16]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Iroquois-class homeodomain protein IRX-1 (IRX1).	[17]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Iroquois-class homeodomain protein IRX-1 (IRX1).	[18]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Iroquois-class homeodomain protein IRX-1 (IRX1).	[19]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Iroquois-class homeodomain protein IRX-1 (IRX1).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Iroquois-class homeodomain protein IRX-1 (IRX1).	[21]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Iroquois-class homeodomain protein IRX-1 (IRX1).	[22]

References

• [1] Investigating Role of IRX Family in Development of Female Adolescent Idiopathic Scoliosis: Which One Is Real Cause?.World Neurosurg. 2019 Jul;127:e132-e136. doi: 10.1016/j.wneu.2019.02.184. Epub 2019 Mar 9.
• [2] Clinical significance of Iroquois Homeobox Gene - IRX1 in human glioma.Mol Med Rep. 2018 Mar;17(3):4651-4656. doi: 10.3892/mmr.2018.8404. Epub 2018 Jan 9.
• [3] Prognostic value of aberrantly expressed methylation gene profiles in lung squamous cell carcinoma: A study based on The Cancer Genome Atlas.J Cell Physiol. 2019 May;234(5):6519-6528. doi: 10.1002/jcp.27389. Epub 2018 Sep 24.
• [4] Iroquois Homeobox 1 Acts as a True Tumor Suppressor in Multiple Organs by Regulating Cell Cycle Progression.Neoplasia. 2019 Oct;21(10):1003-1014. doi: 10.1016/j.neo.2019.08.001. Epub 2019 Aug 23.
• [5] Hypermethylation of EBF3 and IRX1 genes in synovial fibroblasts of patients with rheumatoid arthritis.Mol Cells. 2013 Apr;35(4):298-304. doi: 10.1007/s10059-013-2302-0. Epub 2013 Feb 26.
• [6] Identification of IRX1 as a Risk Locus for Rheumatoid Factor Positivity in Rheumatoid Arthritis in a Genome-Wide Association Study.Arthritis Rheumatol. 2016 Jun;68(6):1384-91. doi: 10.1002/art.39591.
• [7] Gene expression profiling differentiates germ cell tumors from other cancers and defines subtype-specific signatures.Proc Natl Acad Sci U S A. 2005 Dec 6;102(49):17763-8. doi: 10.1073/pnas.0509082102. Epub 2005 Nov 23.
• [8] Frequently methylated tumor suppressor genes in head and neck squamous cell carcinoma.Cancer Res. 2008 Jun 15;68(12):4494-9. doi: 10.1158/0008-5472.CAN-07-6509.
• [9] IRX1 hypomethylation promotes osteosarcoma metastasis via induction of CXCL14/NF-B signaling.J Clin Invest. 2015 May;125(5):1839-56. doi: 10.1172/JCI78437. Epub 2015 Mar 30.
• [10] Protein arginine methyltransferase 5-mediated epigenetic silencing of IRX1 contributes to tumorigenicity and metastasis of gastric cancer.Biochim Biophys Acta Mol Basis Dis. 2018 Sep;1864(9 Pt B):2835-2844. doi: 10.1016/j.bbadis.2018.05.015. Epub 2018 May 23.
• [11] Validation of nucleolar protein 4 as a novel methylated tumor suppressor gene in head and neck cancer.Oncol Rep. 2014 Feb;31(2):1014-20. doi: 10.3892/or.2013.2927. Epub 2013 Dec 16.
• [12] Duplication events downstream of IRX1 cause North Carolina macular dystrophy at the MCDR3 locus.Sci Rep. 2017 Aug 8;7(1):7512. doi: 10.1038/s41598-017-06387-6.
• [13] Expression of Iroquois genes is up-regulated during early lung development in the nitrofen-induced pulmonary hypoplasia.J Pediatr Surg. 2011 Jan;46(1):62-6. doi: 10.1016/j.jpedsurg.2010.09.059.
• [14] 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.
• [15] 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.
• [16] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [17] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [18] 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.
• [19] 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.
• [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] Transcriptomic?pathway?and?benchmark dose analysis of Bisphenol A, Bisphenol S, Bisphenol F, and 3,3',5,5'-Tetrabromobisphenol A in H9 human embryonic stem cells. Toxicol In Vitro. 2021 Apr;72:105097. doi: 10.1016/j.tiv.2021.105097. Epub 2021 Jan 18.
• [22] 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.
• [23] Prediction of doxorubicin sensitivity in breast tumors based on gene expression profiles of drug-resistant cell lines correlates with patient survival. Oncogene. 2005 Nov 17;24(51):7542-51. doi: 10.1038/sj.onc.1208908.