Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBUZ35T)

• DOT Name: Homeobox protein Hox-D3 (HOXD3)
• Synonyms: Homeobox protein Hox-4A
• Gene Name: HOXD3
• Related Disease:
  Acute erythroid leukemia
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Duane retraction syndrome
  Epithelial ovarian cancer
  Hepatocellular carcinoma
  Leukemia
  Lung cancer
  Lung carcinoma
  Melanoma
  Motion sickness
  Neoplasm
  Ovarian cancer
  Ovarian neoplasm
  Promyelocytic leukaemia
  Prostate cancer
  Prostate carcinoma
  Prostate neoplasm
  Benign prostatic hyperplasia
  Clear cell renal carcinoma
  Colorectal carcinoma
  Gastric cancer
  Ovarian serous adenocarcinoma
  Stomach cancer
• UniProt ID: HXD3_HUMAN
• Pfam ID: PF13293 ; PF00046
• Sequence:
  MLFEQGQQALELPECTMQKAAYYENPGLFGGYGYSKTTDTYGYSTPHQPYPPPAAASSLD
  TDYPGSACSIQSSAPLRAPAHKGAELNGSCMRPGTGNSQGGGGGSQPPGLNSEQQPPQPP
  PPPPTLPPSSPTNPGGGVPAKKPKGGPNASSSSATISKQIFPWMKESRQNSKQKNSCATA
  GESCEDKSPPGPASKRVRTAYTSAQLVELEKEFHFNRYLCRPRRVEMANLLNLTERQIKI
  WFQNRRMKYKKDQKAKGILHSPASQSPERSPPLGGAAGHVAYSGQLPPVPGLAYDAPSPP
  AFAKSQPNMYGLAAYTAPLSSCLPQQKRYAAPEFEPHPMASNGGGFASANLQGSPVYVGG
  NFVESMAPASGPVFNLGHLSHPSSASVDYSCAAQIPGNHHHGPCDPHPTYTDLSAHHSSQ
  GRLPEAPKLTHL
• 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

25 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute erythroid leukemia	DISZFC1O	Strong	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[2]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[2]
Duane retraction syndrome	DISOEBK2	Strong	Genetic Variation	[3]
Epithelial ovarian cancer	DIS56MH2	Strong	Genetic Variation	[4]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[5]
Leukemia	DISNAKFL	Strong	Posttranslational Modification	[6]
Lung cancer	DISCM4YA	Strong	Biomarker	[7]
Lung carcinoma	DISTR26C	Strong	Biomarker	[7]
Melanoma	DIS1RRCY	Strong	Biomarker	[8]
Motion sickness	DISZ2WZW	Strong	Genetic Variation	[9]
Neoplasm	DISZKGEW	Strong	Biomarker	[10]
Ovarian cancer	DISZJHAP	Strong	Genetic Variation	[4]
Ovarian neoplasm	DISEAFTY	Strong	Genetic Variation	[11]
Promyelocytic leukaemia	DISYGG13	Strong	Altered Expression	[1]
Prostate cancer	DISF190Y	Strong	Biomarker	[12]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[12]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[13]
Benign prostatic hyperplasia	DISI3CW2	Limited	Biomarker	[14]
Clear cell renal carcinoma	DISBXRFJ	Limited	Posttranslational Modification	[15]
Colorectal carcinoma	DIS5PYL0	Limited	Biomarker	[16]
Gastric cancer	DISXGOUK	Limited	Biomarker	[17]
Ovarian serous adenocarcinoma	DISSU72Z	Limited	Genetic Variation	[11]
Stomach cancer	DISKIJSX	Limited	Biomarker	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Homeobox protein Hox-D3 (HOXD3).	[18]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the expression of Homeobox protein Hox-D3 (HOXD3).	[19]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Homeobox protein Hox-D3 (HOXD3).	[20]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Homeobox protein Hox-D3 (HOXD3).	[21]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Homeobox protein Hox-D3 (HOXD3).	[13]
Indomethacin	DMSC4A7	Approved	Indomethacin decreases the expression of Homeobox protein Hox-D3 (HOXD3).	[23]
Amphotericin B	DMTAJQE	Approved	Amphotericin B decreases the expression of Homeobox protein Hox-D3 (HOXD3).	[24]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Homeobox protein Hox-D3 (HOXD3).	[20]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Homeobox protein Hox-D3 (HOXD3).	[26]
Rutin	DMEHRAJ	Investigative	Rutin increases the expression of Homeobox protein Hox-D3 (HOXD3).	[27]
CATECHIN	DMY38SB	Investigative	CATECHIN increases the expression of Homeobox protein Hox-D3 (HOXD3).	[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 increases the methylation of Homeobox protein Hox-D3 (HOXD3).	[25]

References

• [1] Overexpression of the HOX4A (HOXD3) homeobox gene in human erythroleukemia HEL cells results in altered adhesive properties.Blood. 1995 May 15;85(10):2786-94.
• [2] HOXD3 Plays a Critical Role in Breast Cancer Stemness and Drug Resistance.Cell Physiol Biochem. 2018;46(4):1737-1747. doi: 10.1159/000489249. Epub 2018 Apr 23.
• [3] Interstitial deletion of 1q42.13-q43 with Duane retraction syndrome.J AAPOS. 2007 Feb;11(1):62-4. doi: 10.1016/j.jaapos.2006.09.006. Epub 2006 Nov 22.
• [4] Ovarian cancer variant rs2072590 is associated with HOXD1 and HOXD3 gene expression.Oncotarget. 2017 Oct 13;8(61):103410-103414. doi: 10.18632/oncotarget.21902. eCollection 2017 Nov 28.
• [5] HOXD3 targeted by miR-203a suppresses cell metastasis and angiogenesis through VEGFR in human hepatocellular carcinoma cells.Sci Rep. 2018 Feb 5;8(1):2431. doi: 10.1038/s41598-018-20859-3.
• [6] 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.
• [7] Novel candidate key drivers in the integrative network of genes, microRNAs, methylations, and copy number variations in squamous cell lung carcinoma.Biomed Res Int. 2015;2015:358125. doi: 10.1155/2015/358125. Epub 2015 Feb 23.
• [8] Transduction of HOXD3-antisense into human melanoma cells results in decreased invasive and motile activities.Clin Exp Metastasis. 2002;19(6):503-11. doi: 10.1023/a:1020346211686.
• [9] Genetic variants associated with motion sickness point to roles for inner ear development, neurological processes and glucose homeostasis.Hum Mol Genet. 2015 May 1;24(9):2700-8. doi: 10.1093/hmg/ddv028. Epub 2015 Jan 26.
• [10] Validation study of genes with hypermethylated promoter regions associated with prostate cancer recurrence.Cancer Epidemiol Biomarkers Prev. 2014 Jul;23(7):1331-9. doi: 10.1158/1055-9965.EPI-13-1000. Epub 2014 Apr 9.
• [11] Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer.Nat Genet. 2017 May;49(5):680-691. doi: 10.1038/ng.3826. Epub 2017 Mar 27.
• [12] A urine-based DNA methylation assay, ProCUrE, to identify clinically significant prostate cancer.Clin Epigenetics. 2018 Nov 23;10(1):147. doi: 10.1186/s13148-018-0575-z.
• [13] Discovery of novel hypermethylated genes in prostate cancer using genomic CpG island microarrays. PLoS One. 2009;4(3):e4830. doi: 10.1371/journal.pone.0004830. Epub 2009 Mar 13.
• [14] Methylation of PITX2, HOXD3, RASSF1 and TDRD1 predicts biochemical recurrence in high-risk prostate cancer.J Cancer Res Clin Oncol. 2014 Nov;140(11):1849-61. doi: 10.1007/s00432-014-1738-8. Epub 2014 Jun 18.
• [15] LAT, HOXD3 and NFE2L3 identified as novel DNA methylation-driven genes and prognostic markers in human clear cell renal cell carcinoma by integrative bioinformatics approaches.J Cancer. 2019 Oct 22;10(26):6726-6737. doi: 10.7150/jca.35641. eCollection 2019.
• [16] Nuclear lncRNA HOXD-AS1 suppresses colorectal carcinoma growth and metastasis via inhibiting HOXD3-induced integrin 3 transcriptional activating and MAPK/AKT signalling.Mol Cancer. 2019 Mar 1;18(1):31. doi: 10.1186/s12943-019-0955-9.
• [17] miR-99b-3p is induced by vitamin D3 and contributes to its antiproliferative effects in gastric cancer cells by targeting HoxD3.Biol Chem. 2019 Jul 9;400(8):1079-1086. doi: 10.1515/hsz-2019-0102. Print 2019 Jul 26.
• [18] 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.
• [19] Inorganic arsenic exposure promotes malignant progression by HDAC6-mediated down-regulation of HTRA1. J Appl Toxicol. 2023 Aug;43(8):1214-1224. doi: 10.1002/jat.4457. Epub 2023 Mar 11.
• [20] 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.
• [21] 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.
• [22] Discovery of novel hypermethylated genes in prostate cancer using genomic CpG island microarrays. PLoS One. 2009;4(3):e4830. doi: 10.1371/journal.pone.0004830. Epub 2009 Mar 13.
• [23] Evaluation of developmental toxicity using undifferentiated human embryonic stem cells. J Appl Toxicol. 2015 Feb;35(2):205-18.
• [24] Differential expression of microRNAs and their predicted targets in renal cells exposed to amphotericin B and its complex with copper (II) ions. Toxicol Mech Methods. 2017 Sep;27(7):537-543. doi: 10.1080/15376516.2017.1333554. Epub 2017 Jun 8.
• [25] 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.
• [26] 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.
• [27] Epicatechin and a cocoa polyphenolic extract modulate gene expression in human Caco-2 cells. J Nutr. 2004 Oct;134(10):2509-16.