Details of Drug Off-Target (DOT)

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

• DOT Name: Homeobox protein Hox-A4 (HOXA4)
• Synonyms: Homeobox protein Hox-1.4; Homeobox protein Hox-1D
• Gene Name: HOXA4
• Related Disease:
  Lung adenocarcinoma
  Acute monocytic leukemia
  Advanced cancer
  Blast phase chronic myelogenous leukemia, BCR-ABL1 positive
  Breast cancer
  Carcinoma
  Chromosomal disorder
  Colon cancer
  Colon carcinoma
  Epithelial ovarian cancer
  Glioma
  Hypospadias
  leukaemia
  Lung cancer
  Lung carcinoma
  Neoplasm
  Non-small-cell lung cancer
  Silver-Russell syndrome
  Small lymphocytic lymphoma
  Acute myelogenous leukaemia
  Chronic obstructive pulmonary disease
  Werner syndrome
  Ovarian neoplasm
  Adenocarcinoma
  Breast carcinoma
  Colorectal carcinoma
  Leukemia
  Ovarian cancer
• UniProt ID: HXA4_HUMAN
• Pfam ID: PF00046
• Sequence:
  MTMSSFLINSNYIEPKFPPFEEYAQHSGSGGADGGPGGGPGYQQPPAPPTQHLPLQQPQL
  PHAGGGREPTASYYAPRTAREPAYPAAALYPAHGAADTAYPYGYRGGASPGRPPQPEQPP
  AQAKGPAHGLHASHVLQPQLPPPLQPRAVPPAAPRRCEAAPATPGVPAGGSAPACPLLLA
  DKSPLGLKGKEPVVYPWMKKIHVSAVNPSYNGGEPKRSRTAYTRQQVLELEKEFHFNRYL
  TRRRRIEIAHTLCLSERQVKIWFQNRRMKWKKDHKLPNTKMRSSNSASASAGPPGKAQTQ
  SPHLHPHPHPSTSTPVPSSI
• 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. Binds to sites in the 5'-flanking sequence of its coding region with various affinities. The consensus sequences of the high and low affinity binding sites are 5'-TAATGA[CG]-3' and 5'-CTAATTTT-3'.
• Tissue Specificity: Embryonic nervous system.
• Reactome Pathway: Activation of anterior HOX genes in hindbrain development during early embryogenesis (R-HSA-5617472)

Molecular Interaction Atlas (MIA) of This DOT

28 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Lung adenocarcinoma	DISD51WR	Definitive	Altered Expression	[1]
Acute monocytic leukemia	DIS28NEL	Strong	Altered Expression	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Blast phase chronic myelogenous leukemia, BCR-ABL1 positive	DIS3KLUX	Strong	Biomarker	[4]
Breast cancer	DIS7DPX1	Strong	Posttranslational Modification	[5]
Carcinoma	DISH9F1N	Strong	Altered Expression	[6]
Chromosomal disorder	DISM5BB5	Strong	Altered Expression	[7]
Colon cancer	DISVC52G	Strong	Altered Expression	[8]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[8]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[9]
Glioma	DIS5RPEH	Strong	Biomarker	[3]
Hypospadias	DIS48CCP	Strong	Genetic Variation	[10]
leukaemia	DISS7D1V	Strong	Genetic Variation	[11]
Lung cancer	DISCM4YA	Strong	Altered Expression	[9]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[9]
Neoplasm	DISZKGEW	Strong	Altered Expression	[9]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[12]
Silver-Russell syndrome	DISSVJ1D	Strong	Posttranslational Modification	[13]
Small lymphocytic lymphoma	DIS30POX	Strong	Altered Expression	[14]
Acute myelogenous leukaemia	DISCSPTN	moderate	Posttranslational Modification	[7]
Chronic obstructive pulmonary disease	DISQCIRF	moderate	Genetic Variation	[15]
Werner syndrome	DISZY45W	moderate	Biomarker	[16]
Ovarian neoplasm	DISEAFTY	Disputed	Altered Expression	[17]
Adenocarcinoma	DIS3IHTY	Limited	Altered Expression	[17]
Breast carcinoma	DIS2UE88	Limited	Posttranslational Modification	[5]
Colorectal carcinoma	DIS5PYL0	Limited	Biomarker	[18]
Leukemia	DISNAKFL	Limited	Posttranslational Modification	[4]
Ovarian cancer	DISZJHAP	Limited	Altered Expression	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Homeobox protein Hox-A4 (HOXA4).	[19]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Homeobox protein Hox-A4 (HOXA4).	[20]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Homeobox protein Hox-A4 (HOXA4).	[21]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Homeobox protein Hox-A4 (HOXA4).	[22]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Homeobox protein Hox-A4 (HOXA4).	[23]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Homeobox protein Hox-A4 (HOXA4).	[24]
DTI-015	DMXZRW0	Approved	DTI-015 decreases the expression of Homeobox protein Hox-A4 (HOXA4).	[25]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Homeobox protein Hox-A4 (HOXA4).	[27]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Homeobox protein Hox-A4 (HOXA4).	[26]

References

• [1] HOXA4-Dependent Transcriptional Activation of AXL Promotes Cisplatin- Resistance in Lung Adenocarcinoma Cells.Anticancer Agents Med Chem. 2018;18(14):2062-2067. doi: 10.2174/1871520619666181203110835.
• [2] The combined expression of HOXA4 and MEIS1 is an independent prognostic factor in patients with AML.Eur J Haematol. 2009 Nov;83(5):439-48. doi: 10.1111/j.1600-0609.2009.01309.x. Epub 2009 Jun 25.
• [3] Long Non-Coding RNA HOXA-AS2 Enhances The Malignant Biological Behaviors In Glioma By Epigenetically Regulating RND3 Expression.Onco Targets Ther. 2019 Nov 7;12:9407-9419. doi: 10.2147/OTT.S225678. eCollection 2019.
• [4] Inactivation of HOXA genes by hypermethylation in myeloid and lymphoid malignancy is frequent and associated with poor prognosis.Clin Cancer Res. 2007 Sep 1;13(17):5048-55. doi: 10.1158/1078-0432.CCR-07-0919.
• [5] Microarray-based analysis of whole-genome DNA methylation profiling in early detection of breast cancer.J Cell Biochem. 2019 Jan;120(1):658-670. doi: 10.1002/jcb.27423. Epub 2018 Sep 11.
• [6] Identification of a developmental gene expression signature, including HOX genes, for the normal human colonic crypt stem cell niche: overexpression of the signature parallels stem cell overpopulation during colon tumorigenesis.Stem Cells Dev. 2014 Jan 15;23(2):167-79. doi: 10.1089/scd.2013.0039. Epub 2013 Nov 5.
• [7] Promoter DNA methylation and expression levels of HOXA4, HOXA5 and MEIS1 in acute myeloid leukemia.Mol Med Rep. 2015 May;11(5):3948-54. doi: 10.3892/mmr.2015.3196. Epub 2015 Jan 13.
• [8] Overexpression of HOXA4 and HOXA9 genes promotes self-renewal and contributes to colon cancer stem cell overpopulation.J Cell Physiol. 2018 Feb;233(2):727-735. doi: 10.1002/jcp.25981. Epub 2017 Jul 11.
• [9] HOXA4, down-regulated in lung cancer, inhibits the growth, motility and invasion of lung cancer cells.Cell Death Dis. 2018 May 1;9(5):465. doi: 10.1038/s41419-018-0497-x.
• [10] 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.
• [11] 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.
• [12] HOXA4-regulated miR-138 suppresses proliferation and gefitinib resistance in non-small cell lung cancer.Mol Genet Genomics. 2019 Feb;294(1):85-93. doi: 10.1007/s00438-018-1489-3. Epub 2018 Sep 8.
• [13] Hypomethylation of HOXA4 promoter is common in Silver-Russell syndrome and growth restriction and associates with stature in healthy children.Sci Rep. 2017 Nov 16;7(1):15693. doi: 10.1038/s41598-017-16070-5.
• [14] Promoter hypermethylation silences expression of the HoxA4 gene and correlates with IgVh mutational status in CLL.Leukemia. 2006 Jul;20(7):1326-9. doi: 10.1038/sj.leu.2404254. Epub 2006 May 11.
• [15] Relationship between COPD and polymorphisms of HOX-1 and mEPH in a Chinese population.Oncol Rep. 2007 Feb;17(2):483-8.
• [16] 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.
• [17] Expression and function of HOXA genes in normal and neoplastic ovarian epithelial cells.Differentiation. 2009 Feb;77(2):162-71. doi: 10.1016/j.diff.2008.09.018. Epub 2008 Oct 25.
• [18] Gene expression signatures for HOXA4, HOXA9, and HOXD10 reveal alterations in transcriptional regulatory networks in colon cancer.J Cell Physiol. 2019 Aug;234(8):13042-13056. doi: 10.1002/jcp.27975. Epub 2018 Dec 14.
• [19] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [20] 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.
• [21] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [22] 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.
• [23] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [24] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [25] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [26] 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.
• [27] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.