Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2DKIDK)

• DOT Name: Homeobox protein engrailed-1 (EN1)
• Synonyms: Homeobox protein en-1; Hu-En-1
• Gene Name: EN1
• Related Disease:
  Epithelial neoplasm
  Schizophrenia
  Sweat gland neoplasm
  Aplasia cutis congenita
  Corpus callosum, agenesis of
  Endove syndrome, limb-only type
  Neoplasm
  Nervous system disease
• UniProt ID: HME1_HUMAN
• Pfam ID: PF10525 ; PF00046
• Sequence:
  MEEQQPEPKSQRDSALGAAAAATPGGLSLSLSPGASGSSGSGSDGDSVPVSPQPAPPSPP
  AAPCLPPLAHHPHLPPHPPPPPPQHLAAPAHQPQPAAQLHRTTNFFIDNILRPDFGCKKE
  QPPPQLLVAAAARGGAGGGGRVERDRGQTAAGRDPVHPLGTRAPGAASLLCAPDANCGPP
  DGSQPAAAGAGASKAGNPAAAAAAAAAAVAAAAAAAAAKPSDTGGGGSGGGAGSPGAQGT
  KYPEHGNPAILLMGSANGGPVVKTDSQQPLVWPAWVYCTRYSDRPSSGPRTRKLKKKKNE
  KEDKRPRTAFTAEQLQRLKAEFQANRYITEQRRQTLAQELSLNESQIKIWFQNKRAKIKK
  ATGIKNGLALHLMAQGLYNHSTTTVQDKDESE
• Function: Required for proper formation of the apical ectodermal ridge and correct dorsal-ventral patterning in the limb.

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 neoplasm	DIS0T594	Strong	Altered Expression	[1]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[2]
Sweat gland neoplasm	DISQ2Y02	Strong	Altered Expression	[1]
Aplasia cutis congenita	DISMDAYM	Limited	Biomarker	[3]
Corpus callosum, agenesis of	DISO9P40	Limited	Biomarker	[3]
Endove syndrome, limb-only type	DIS4FE14	Limited	Unknown	[4]
Neoplasm	DISZKGEW	Limited	Posttranslational Modification	[3]
Nervous system disease	DISJ7GGT	Limited	Biomarker	[5]

8 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 engrailed-1 (EN1).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Homeobox protein engrailed-1 (EN1).	[7]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Homeobox protein engrailed-1 (EN1).	[8]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Homeobox protein engrailed-1 (EN1).	[9]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Homeobox protein engrailed-1 (EN1).	[6]
Malathion	DMXZ84M	Approved	Malathion decreases the expression of Homeobox protein engrailed-1 (EN1).	[11]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Homeobox protein engrailed-1 (EN1).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Homeobox protein engrailed-1 (EN1).	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the methylation of Homeobox protein engrailed-1 (EN1).	[10]

References

• [1] Homeobox transcriptional factor engrailed homeobox 1 is expressed specifically in normal and neoplastic sweat gland cells.Histopathology. 2018 Jun;72(7):1199-1208. doi: 10.1111/his.13486. Epub 2018 Mar 25.
• [2] Model-based gene selection shows engrailed 1 is associated with antipsychotic response.Pharmacogenet Genomics. 2008 Sep;18(9):751-9. doi: 10.1097/FPC.0b013e32830162bc.
• [3] Developmental transcription factor EN1--a novel biomarker in human salivary gland adenoid cystic carcinoma.Cancer. 2012 Mar 1;118(5):1288-92. doi: 10.1002/cncr.26412. Epub 2011 Jul 28.
• [4] Non-coding deletions identify Maenli lncRNA as a limb-specific En1 regulator. Nature. 2021 Apr;592(7852):93-98. doi: 10.1038/s41586-021-03208-9. Epub 2021 Feb 10.
• [5] Engrailed protects mouse midbrain dopaminergic neurons against mitochondrial complex I insults.Nat Neurosci. 2011 Sep 4;14(10):1260-6. doi: 10.1038/nn.2916.
• [6] Neuronal and cardiac toxicity of pharmacological compounds identified through transcriptomic analysis of human pluripotent stem cell-derived embryoid bodies. Toxicol Appl Pharmacol. 2021 Dec 15;433:115792. doi: 10.1016/j.taap.2021.115792. Epub 2021 Nov 3.
• [7] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [8] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [9] 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.
• [10] 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.
• [11] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [12] Differential regulation of proliferation, cell cycle control and gene expression in cultured human aortic and pulmonary artery endothelial cells by resveratrol. Int J Mol Med. 2010 Nov;26(5):743-9.