Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTIX5XFB)

• DOT Name: Homeobox protein Hox-A3 (HOXA3)
• Synonyms: Homeobox protein Hox-1E
• Gene Name: HOXA3
• Related Disease:
  Type-1/2 diabetes
  Acute myelogenous leukaemia
  Colon cancer
  Colon carcinoma
  Colonic neoplasm
  DiGeorge syndrome
  Glioma
  High blood pressure
  Hypospadias
  leukaemia
  Leukemia
  Lung adenocarcinoma
  Lymphatic malformation
  Non-small-cell lung cancer
  Thyroid gland papillary carcinoma
  Chronic obstructive pulmonary disease
  Meningioma
  Werner syndrome
  Clear cell renal carcinoma
  Neoplasm
• UniProt ID: HXA3_HUMAN
• Pfam ID: PF13293 ; PF00046
• Sequence:
  MQKATYYDSSAIYGGYPYQAANGFAYNANQQPYPASAALGADGEYHRPACSLQSPSSAGG
  HPKAHELSEACLRTLSAPPSQPPSLGEPPLHPPPPQAAPPAPQPPQPAPQPPAPTPAAPP
  PPSSASPPQNASNNPTPANAAKSPLLNSPTVAKQIFPWMKESRQNTKQKTSSSSSGESCA
  GDKSPPGQASSKRARTAYTSAQLVELEKEFHFNRYLCRPRRVEMANLLNLTERQIKIWFQ
  NRRMKYKKDQKGKGMLTSSGGQSPSRSPVPPGAGGYLNSMHSLVNSVPYEPQSPPPFSKP
  PQGTYGLPPASYPASLPSCAPPPPPQKRYTAAGAGAGGTPDYDPHAHGLQGNGSYGTPHI
  QGSPVFVGGSYVEPMSNSGPALFGLTHLPHAASGAMDYGGAGPLGSGHHHGPGPGEPHPT
  YTDLTGHHPSQGRIQEAPKLTHL
• Function: Sequence-specific transcription factor which is part of a developmental regulatory system that provides cells with specific positional identities on the anterior-posterior axis.
• Reactome Pathway: Activation of anterior HOX genes in hindbrain development during early embryogenesis (R-HSA-5617472)

Molecular Interaction Atlas (MIA) of This DOT

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Type-1/2 diabetes	DISIUHAP	Definitive	Biomarker	[1]
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[2]
Colon cancer	DISVC52G	Strong	Altered Expression	[3]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[3]
Colonic neoplasm	DISSZ04P	Strong	Altered Expression	[3]
DiGeorge syndrome	DIST1RKO	Strong	Biomarker	[4]
Glioma	DIS5RPEH	Strong	Biomarker	[5]
High blood pressure	DISY2OHH	Strong	Genetic Variation	[6]
Hypospadias	DIS48CCP	Strong	Genetic Variation	[7]
leukaemia	DISS7D1V	Strong	Genetic Variation	[8]
Leukemia	DISNAKFL	Strong	Genetic Variation	[8]
Lung adenocarcinoma	DISD51WR	Strong	Altered Expression	[9]
Lymphatic malformation	DIS4D8VL	Strong	Biomarker	[10]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[9]
Thyroid gland papillary carcinoma	DIS48YMM	Strong	Biomarker	[11]
Chronic obstructive pulmonary disease	DISQCIRF	moderate	Genetic Variation	[12]
Meningioma	DISPT4TG	moderate	Biomarker	[13]
Werner syndrome	DISZY45W	moderate	Biomarker	[14]
Clear cell renal carcinoma	DISBXRFJ	Limited	Biomarker	[15]
Neoplasm	DISZKGEW	Limited	Biomarker	[15]

9 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 Homeobox protein Hox-A3 (HOXA3).	[16]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Homeobox protein Hox-A3 (HOXA3).	[17]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Homeobox protein Hox-A3 (HOXA3).	[18]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Homeobox protein Hox-A3 (HOXA3).	[19]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Homeobox protein Hox-A3 (HOXA3).	[20]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Homeobox protein Hox-A3 (HOXA3).	[21]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Homeobox protein Hox-A3 (HOXA3).	[22]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Homeobox protein Hox-A3 (HOXA3).	[23]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Homeobox protein Hox-A3 (HOXA3).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Homeobox protein Hox-A3 (HOXA3).	[25]

References

• [1] Dysregulation of macrophage development and phenotype in diabetic human macrophages can be rescued by Hoxa3 protein transduction.PLoS One. 2019 Oct 18;14(10):e0223980. doi: 10.1371/journal.pone.0223980. eCollection 2019.
• [2] The Role of the HOXA Gene Family in Acute Myeloid Leukemia.Genes (Basel). 2019 Aug 16;10(8):621. doi: 10.3390/genes10080621.
• [3] HOXA3 promotes tumor growth of human colon cancer through activating EGFR/Ras/Raf/MEK/ERK signaling pathway.J Cell Biochem. 2018 Mar;119(3):2864-2874. doi: 10.1002/jcb.26461. Epub 2017 Dec 12.
• [4] Mouse and zebrafish Hoxa3 orthologues have nonequivalent in vivo protein function.Proc Natl Acad Sci U S A. 2010 Jun 8;107(23):10555-60. doi: 10.1073/pnas.1005129107. Epub 2010 May 24.
• [5] Quantitative methylation analysis of HOXA3, 7, 9, and 10 genes in glioma: association with tumor WHO grade and clinical outcome.J Cancer Res Clin Oncol. 2012 Jan;138(1):35-47. doi: 10.1007/s00432-011-1070-5. Epub 2011 Sep 27.
• [6] Single-trait and multi-trait genome-wide association analyses identify novel loci for blood pressure in African-ancestry populations.PLoS Genet. 2017 May 12;13(5):e1006728. doi: 10.1371/journal.pgen.1006728. eCollection 2017 May.
• [7] Genome-wide association analyses identify variants in developmental genes associated with hypospadias.Nat Genet. 2014 Sep;46(9):957-63. doi: 10.1038/ng.3063. Epub 2014 Aug 10.
• [8] Lineage and stage specific expression of HOX 1 genes in the human hematopoietic system.Biochem Biophys Res Commun. 1992 Mar 31;183(3):1124-30. doi: 10.1016/s0006-291x(05)80307-9.
• [9] Downregulation of HOXA3 in lung adenocarcinoma and its relevant molecular mechanism analysed by RT-qPCR, TCGA and in silico analysis.Int J Oncol. 2018 Oct;53(4):1557-1579. doi: 10.3892/ijo.2018.4508. Epub 2018 Jul 30.
• [10] Regionally restricted developmental defects resulting from targeted disruption of the mouse homeobox gene hox-1.5.Nature. 1991 Apr 11;350(6318):473-9. doi: 10.1038/350473a0.
• [11] LncRNA HOXA-AS2 Facilitates Tumorigenesis and Progression of Papillary Thyroid Cancer by Modulating the miR-15a-5p/HOXA3 Axis.Hum Gene Ther. 2019 May;30(5):618-631. doi: 10.1089/hum.2018.109. Epub 2019 Feb 26.
• [12] Relationship between COPD and polymorphisms of HOX-1 and mEPH in a Chinese population.Oncol Rep. 2007 Feb;17(2):483-8.
• [13] HOXA7, 9, and 10 are methylation targets associated with aggressive behavior in meningiomas.Transl Res. 2012 Nov;160(5):355-62. doi: 10.1016/j.trsl.2012.05.007. Epub 2012 Jun 23.
• [14] Common and cell type-specific responses of human cells to mitochondrial dysfunction.Exp Cell Res. 2005 Jan 15;302(2):270-80. doi: 10.1016/j.yexcr.2004.09.006.
• [15] miR-10b suppresses cell invasion and metastasis through targeting HOXA3 regulated by FAK/YAP signaling pathway in clear-cell renal cell carcinoma.BMC Nephrol. 2019 Apr 11;20(1):127. doi: 10.1186/s12882-019-1322-1.
• [16] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [17] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [18] Noncoding RNA synthesis and loss of Polycomb group repression accompanies the colinear activation of the human HOXA cluster. RNA. 2007 Feb;13(2):223-39. doi: 10.1261/rna.266707. Epub 2006 Dec 21.
• [19] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [20] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [21] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [22] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [23] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [24] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [25] 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.