Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTN4V9ZF)

• DOT Name: Homeobox protein Hox-D1 (HOXD1)
• Synonyms: Homeobox protein Hox-GG
• Gene Name: HOXD1
• Related Disease:
  Epithelial ovarian cancer
  Ovarian cancer
  Ovarian neoplasm
  Breast cancer
  Breast carcinoma
  Colorectal carcinoma
  Colorectal neoplasm
  Neuroblastoma
• UniProt ID: HXD1_HUMAN
• Pfam ID: PF00046
• Sequence:
  MSSYLEYVSCSSSGGVGGDVLSLAPKFCRSDARPVALQPAFPLGNGDGAFVSCLPLAAAR
  PSPSPPAAPARPSVPPPAAPQYAQCTLEGAYEPGAAPAAAAGGADYGFLGSGPAYDFPGV
  LGRAADDGGSHVHYATSAVFSGGGSFLLSGQVDYAAFGEPGPFPACLKASADGHPGAFQT
  ASPAPGTYPKSVSPASGLPAAFSTFEWMKVKRNASKKGKLAEYGAASPSSAIRTNFSTKQ
  LTELEKEFHFNKYLTRARRIEIANCLHLNDTQVKIWFQNRRMKQKKREREGLLATAIPVA
  PLQLPLSGTTPTKFIKNPGSPSQSQEPS
• 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. Acts on the anterior body structures.
• KEGG Pathway: Sig.ling pathways regulating pluripotency of stem cells (hsa04550)
• Reactome Pathway: Activation of anterior HOX genes in hindbrain development during early embryogenesis (R-HSA-5617472)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Epithelial ovarian cancer	DIS56MH2	Strong	Genetic Variation	[1]
Ovarian cancer	DISZJHAP	Strong	Genetic Variation	[1]
Ovarian neoplasm	DISEAFTY	Strong	Genetic Variation	[1]
Breast cancer	DIS7DPX1	moderate	Biomarker	[2]
Breast carcinoma	DIS2UE88	moderate	Biomarker	[2]
Colorectal carcinoma	DIS5PYL0	Disputed	Biomarker	[3]
Colorectal neoplasm	DISR1UCN	Disputed	Biomarker	[3]
Neuroblastoma	DISVZBI4	Limited	Altered Expression	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Homeobox protein Hox-D1 (HOXD1).	[5]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Homeobox protein Hox-D1 (HOXD1).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Homeobox protein Hox-D1 (HOXD1).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Homeobox protein Hox-D1 (HOXD1).	[8]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Homeobox protein Hox-D1 (HOXD1).	[10]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Homeobox protein Hox-D1 (HOXD1).	[11]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Homeobox protein Hox-D1 (HOXD1).	[11]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of Homeobox protein Hox-D1 (HOXD1).	[12]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Homeobox protein Hox-D1 (HOXD1).	[13]
Ethanol	DMDRQZU	Approved	Ethanol decreases the expression of Homeobox protein Hox-D1 (HOXD1).	[14]
Indomethacin	DMSC4A7	Approved	Indomethacin decreases the expression of Homeobox protein Hox-D1 (HOXD1).	[12]
Melphalan	DMOLNHF	Approved	Melphalan increases the expression of Homeobox protein Hox-D1 (HOXD1).	[15]
Ampicillin	DMHWE7P	Approved	Ampicillin increases the expression of Homeobox protein Hox-D1 (HOXD1).	[10]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Homeobox protein Hox-D1 (HOXD1).	[16]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Homeobox protein Hox-D1 (HOXD1).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Homeobox protein Hox-D1 (HOXD1).	[19]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Homeobox protein Hox-D1 (HOXD1).	[20]
Resorcinol	DMM37C0	Investigative	Resorcinol increases the expression of Homeobox protein Hox-D1 (HOXD1).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Homeobox protein Hox-D1 (HOXD1).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Homeobox protein Hox-D1 (HOXD1).	[17]

References

• [1] 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.
• [2] Biomarkers for detection and prognosis of breast cancer identified by a functional hypermethylome screen.Epigenetics. 2012 Jul;7(7):701-9. doi: 10.4161/epi.20445. Epub 2012 Jul 1.
• [3] Comparing the DNA hypermethylome with gene mutations in human colorectal cancer.PLoS Genet. 2007 Sep;3(9):1709-23. doi: 10.1371/journal.pgen.0030157. Epub 2007 Jul 31.
• [4] Up-regulation of HOXC6, HOXD1, and HOXD8 homeobox gene expression in human neuroblastoma cells following chemical induction of differentiation.Tumour Biol. 1996;17(1):34-47. doi: 10.1159/000217965.
• [5] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [6] 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.
• [7] 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.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [10] 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.
• [11] Time series analysis of oxidative stress response patterns in HepG2: a toxicogenomics approach. Toxicology. 2013 Apr 5;306:24-34.
• [12] Evaluation of developmental toxicity using undifferentiated human embryonic stem cells. J Appl Toxicol. 2015 Feb;35(2):205-18.
• [13] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [14] Gene expression signatures after ethanol exposure in differentiating embryoid bodies. Toxicol In Vitro. 2018 Feb;46:66-76.
• [15] Bone marrow osteoblast damage by chemotherapeutic agents. PLoS One. 2012;7(2):e30758. doi: 10.1371/journal.pone.0030758. Epub 2012 Feb 17.
• [16] 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.
• [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] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [19] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [20] 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.