Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0TV6WK)

• DOT Name: Iroquois-class homeodomain protein IRX-4 (IRX4)
• Synonyms: Homeodomain protein IRXA3; Iroquois homeobox protein 4
• Gene Name: IRX4
• Related Disease:
  Neoplasm
  Prostate cancer
  Prostate carcinoma
  Benign prostatic hyperplasia
  Cardiomyopathy
  Cardiovascular disease
  Congenital heart disease
  Ventricular septal defect
  Ventricular septal defect 1
• UniProt ID: IRX4_HUMAN
• Pfam ID: PF05920
• Sequence:
  MSYPQFGYPYSSAPQFLMATNSLSTCCESGGRTLADSGPAASAQAPVYCPVYESRLLATA
  RHELNSAAALGVYGGPYGGSQGYGNYVTYGSEASAFYSLNSFDSKDGSGSAHGGLAPAAA
  AYYPYEPALGQYPYDRYGTMDSGTRRKNATRETTSTLKAWLQEHRKNPYPTKGEKIMLAI
  ITKMTLTQVSTWFANARRRLKKENKMTWPPRNKCADEKRPYAEGEEEEGGEEEAREEPLK
  SSKNAEPVGKEEKELELSDLDDFDPLEAEPPACELKPPFHSLDGGLERVPAAPDGPVKEA
  SGALRMSLAAGGGAALDEDLERARSCLRSAAAGPEPLPGAEGGPQVCEAKLGFVPAGASA
  GLEAKPRIWSLAHTATAAAAAATSLSQTEFPSCMLKRQGPAAPAAVSSAPATSPSVALPH
  SGALDRHQDSPVTSLRNWVDGVFHDPILRHSTLNQAWATAKGALLDPGPLGRSLGAGANV
  LTAPLARAFPPAVPQDAPAAGAARELLALPKAGGKPFCA
• Function: Likely to be an important mediator of ventricular differentiation during cardiac development.
• Tissue Specificity: Predominantly expressed in cardiac ventricles.

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neoplasm	DISZKGEW	Definitive	Biomarker	[1]
Prostate cancer	DISF190Y	Definitive	Altered Expression	[2]
Prostate carcinoma	DISMJPLE	Definitive	Altered Expression	[2]
Benign prostatic hyperplasia	DISI3CW2	Strong	Genetic Variation	[3]
Cardiomyopathy	DISUPZRG	Strong	Biomarker	[4]
Cardiovascular disease	DIS2IQDX	Strong	Genetic Variation	[5]
Congenital heart disease	DISQBA23	Limited	Autosomal dominant	[6]
Ventricular septal defect	DISICO41	Limited	Biomarker	[4]
Ventricular septal defect 1	DISTNZ5D	Limited	Autosomal dominant	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Iroquois-class homeodomain protein IRX-4 (IRX4).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Iroquois-class homeodomain protein IRX-4 (IRX4).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Iroquois-class homeodomain protein IRX-4 (IRX4).	[19]

14 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-4 (IRX4).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Iroquois-class homeodomain protein IRX-4 (IRX4).	[9]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Iroquois-class homeodomain protein IRX-4 (IRX4).	[10]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Iroquois-class homeodomain protein IRX-4 (IRX4).	[11]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Iroquois-class homeodomain protein IRX-4 (IRX4).	[12]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Iroquois-class homeodomain protein IRX-4 (IRX4).	[13]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Iroquois-class homeodomain protein IRX-4 (IRX4).	[14]
Etoposide	DMNH3PG	Approved	Etoposide decreases the expression of Iroquois-class homeodomain protein IRX-4 (IRX4).	[15]
Mitoxantrone	DMM39BF	Approved	Mitoxantrone decreases the expression of Iroquois-class homeodomain protein IRX-4 (IRX4).	[9]
Daunorubicin	DMQUSBT	Approved	Daunorubicin decreases the expression of Iroquois-class homeodomain protein IRX-4 (IRX4).	[9]
Beta-carotene	DM0RXBT	Approved	Beta-carotene decreases the expression of Iroquois-class homeodomain protein IRX-4 (IRX4).	[16]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Iroquois-class homeodomain protein IRX-4 (IRX4).	[18]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Iroquois-class homeodomain protein IRX-4 (IRX4).	[20]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Iroquois-class homeodomain protein IRX-4 (IRX4).	[21]

References

• [1] IRX4 at 5p15 suppresses prostate cancer growth through the interaction with vitamin D receptor, conferring prostate cancer susceptibility.Hum Mol Genet. 2012 May 1;21(9):2076-85. doi: 10.1093/hmg/dds025. Epub 2012 Feb 8.
• [2] Variants at IRX4 as prostate cancer expression quantitative trait loci.Eur J Hum Genet. 2014 Apr;22(4):558-63. doi: 10.1038/ejhg.2013.195. Epub 2013 Sep 11.
• [3] Genetic variants in 2q31 and 5p15 are associated with aggressive benign prostatic hyperplasia in a Chinese population.Prostate. 2013 Aug;73(11):1182-90. doi: 10.1002/pros.22666. Epub 2013 Apr 26.
• [4] Two novel mutations of the IRX4 gene in patients with congenital heart disease. Hum Genet. 2011 Nov;130(5):657-62. doi: 10.1007/s00439-011-0996-7. Epub 2011 May 5.
• [5] Genetic determinants of cardiovascular events among women with migraine: a genome-wide association study.PLoS One. 2011;6(7):e22106. doi: 10.1371/journal.pone.0022106. Epub 2011 Jul 14.
• [6] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [7] 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.
• [8] Atrial-like Engineered Heart Tissue: An In?Vitro Model of the Human Atrium. Stem Cell Reports. 2018 Dec 11;11(6):1378-1390. doi: 10.1016/j.stemcr.2018.10.008. Epub 2018 Nov 8.
• [9] Identification of genomic biomarkers for anthracycline-induced cardiotoxicity in human iPSC-derived cardiomyocytes: an in vitro repeated exposure toxicity approach for safety assessment. Arch Toxicol. 2016 Nov;90(11):2763-2777.
• [10] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [11] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [12] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [13] A genome-wide screen for promoter methylation in lung cancer identifies novel methylation markers for multiple malignancies. PLoS Med. 2006 Dec;3(12):e486. doi: 10.1371/journal.pmed.0030486.
• [14] Progesterone regulation of implantation-related genes: new insights into the role of oestrogen. Cell Mol Life Sci. 2007 Apr;64(7-8):1009-32.
• [15] Cell death mechanisms of the anti-cancer drug etoposide on human cardiomyocytes isolated from pluripotent stem cells. Arch Toxicol. 2018 Apr;92(4):1507-1524.
• [16] Beta-carotene and apocarotenals promote retinoid signaling in BEAS-2B human bronchioepithelial cells. Arch Biochem Biophys. 2006 Nov 1;455(1):48-60.
• [17] 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.
• [18] Synergistic effect of JQ1 and rapamycin for treatment of human osteosarcoma. Int J Cancer. 2015 May 1;136(9):2055-64.
• [19] 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.
• [20] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [21] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.