Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7EZCM2)

• DOT Name: Homeobox protein engrailed-2 (EN2)
• Synonyms: Homeobox protein en-2; Hu-En-2
• Gene Name: EN2
• Related Disease:
  Adenocarcinoma
  Autism
  Autism spectrum disorder
  Bladder cancer
  Blast phase chronic myelogenous leukemia, BCR-ABL1 positive
  Breast neoplasm
  Cytomegalovirus infection
  Epithelial ovarian cancer
  Glioma
  Medulloblastoma
  Non-small-cell lung cancer
  Ovarian cancer
  Ovarian neoplasm
  Pervasive developmental disorder
  Prostate cancer
  Prostate carcinoma
  Urinary bladder cancer
  Urinary bladder neoplasm
  Advanced cancer
  Language disorder
  Neoplasm
  Neurodevelopmental disorder
  Complex neurodevelopmental disorder
  Breast cancer
  Breast carcinoma
  Clear cell renal carcinoma
  Renal cell carcinoma
  Young-onset Parkinson disease
• UniProt ID: HME2_HUMAN
• Pfam ID: PF10525 ; PF00046
• Sequence:
  MEENDPKPGEAAAAVEGQRQPESSPGGGSGGGGGSSPGEADTGRRRALMLPAVLQAPGNH
  QHPHRITNFFIDNILRPEFGRRKDAGTCCAGAGGGRGGGAGGEGGASGAEGGGGAGGSEQ
  LLGSGSREPRQNPPCAPGAGGPLPAAGSDSPGDGEGGSKTLSLHGGAKKGGDPGGPLDGS
  LKARGLGGGDLSVSSDSDSSQAGANLGAQPMLWPAWVYCTRYSDRPSSGPRSRKPKKKNP
  NKEDKRPRTAFTAEQLQRLKAEFQTNRYLTEQRRQSLAQELSLNESQIKIWFQNKRAKIK
  KATGNKNTLAVHLMAQGLYNHSTTAKEGKSDSE

Molecular Interaction Atlas (MIA) of This DOT

28 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adenocarcinoma	DIS3IHTY	Strong	Altered Expression	[1]
Autism	DISV4V1Z	Strong	Genetic Variation	[2]
Autism spectrum disorder	DISXK8NV	Strong	Biomarker	[2]
Bladder cancer	DISUHNM0	Strong	Biomarker	[3]
Blast phase chronic myelogenous leukemia, BCR-ABL1 positive	DIS3KLUX	Strong	Biomarker	[4]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[5]
Cytomegalovirus infection	DISCEMGC	Strong	Biomarker	[6]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[7]
Glioma	DIS5RPEH	Strong	Altered Expression	[6]
Medulloblastoma	DISZD2ZL	Strong	Altered Expression	[8]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[1]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[7]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[7]
Pervasive developmental disorder	DIS51975	Strong	Genetic Variation	[9]
Prostate cancer	DISF190Y	Strong	Biomarker	[10]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[10]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[3]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[3]
Advanced cancer	DISAT1Z9	moderate	Altered Expression	[11]
Language disorder	DISTLKP7	moderate	Biomarker	[12]
Neoplasm	DISZKGEW	moderate	Biomarker	[10]
Neurodevelopmental disorder	DIS372XH	moderate	Genetic Variation	[13]
Complex neurodevelopmental disorder	DISB9AFI	Disputed	Autosomal dominant	[14]
Breast cancer	DIS7DPX1	Limited	Biomarker	[15]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[15]
Clear cell renal carcinoma	DISBXRFJ	Limited	Genetic Variation	[16]
Renal cell carcinoma	DISQZ2X8	Limited	Altered Expression	[15]
Young-onset Parkinson disease	DIS05LFS	Limited	Genetic Variation	[17]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Etoposide	DMNH3PG	Approved	Homeobox protein engrailed-2 (EN2) affects the response to substance of Etoposide.	[22]
Mitoxantrone	DMM39BF	Approved	Homeobox protein engrailed-2 (EN2) affects the response to substance of Mitoxantrone.	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Homeobox protein engrailed-2 (EN2).	[18]
Calphostin C	DM9X2D0	Terminated	Calphostin C affects the expression of Homeobox protein engrailed-2 (EN2).	[20]
CH-223191	DMMJZYC	Investigative	CH-223191 decreases the expression of Homeobox protein engrailed-2 (EN2).	[21]

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 engrailed-2 (EN2).	[19]

References

• [1] Expression of engrailed homeobox 2 regulates the proliferation, migration and invasion of non-small cell lung cancer cells.Oncol Lett. 2018 Jul;16(1):536-542. doi: 10.3892/ol.2018.8693. Epub 2018 May 10.
• [2] Retinal defects in mice lacking the autism-associated gene Engrailed-2.Neuroscience. 2019 Jun 1;408:177-190. doi: 10.1016/j.neuroscience.2019.03.061. Epub 2019 Apr 10.
• [3] Repression of engrailed 2 inhibits the proliferation and invasion of human bladder cancer in vitro and in vivo.Oncol Rep. 2015 May;33(5):2319-30. doi: 10.3892/or.2015.3858. Epub 2015 Mar 17.
• [4] Lineage-specific function of Engrailed-2 in the progression of chronic myelogenous leukemia to T-cell blast crisis.Cell Cycle. 2014;13(11):1717-26. doi: 10.4161/cc.28629. Epub 2014 Mar 25.
• [5] EN2 is a candidate oncogene in human breast cancer.Oncogene. 2005 Oct 20;24(46):6890-901. doi: 10.1038/sj.onc.1208840.
• [6] Hsa-miR-27b is up-regulated in cytomegalovirus-infected human glioma cells, targets engrailed-2 and inhibits its expression.Exp Biol Med (Maywood). 2017 Jun;242(12):1227-1233. doi: 10.1177/1535370217699535. Epub 2017 Mar 26.
• [7] Engrailed-2 (EN2) - a novel biomarker in epithelial ovarian cancer.BMC Cancer. 2018 Oct 3;18(1):943. doi: 10.1186/s12885-018-4816-5.
• [8] Overexpression of Pax5 is not sufficient for neoplastic transformation of mouse neuroectoderm.Int J Cancer. 2001 Aug 15;93(4):459-67. doi: 10.1002/ijc.1371.
• [9] Whole-exome sequencing identifies a novel heterozygous missense variant of the EN2 gene in two unrelated patients with autism spectrum disorder.Psychiatr Genet. 2016 Dec;26(6):297-301. doi: 10.1097/YPG.0000000000000153.
• [10] Is Engrailed-2 (EN2) a truly promising biomarker in prostate cancer detection?.Biomarkers. 2020 Feb;25(1):34-39. doi: 10.1080/1354750X.2019.1690047. Epub 2019 Nov 14.
• [11] Importance of HOX genes in normal prostate gland formation, prostate cancer development and its early detection.BJU Int. 2014 Apr;113(4):535-40. doi: 10.1111/bju.12269. Epub 2013 Aug 13.
• [12] The WNT2 gene polymorphism associated with speech delay inherent to autism.Res Dev Disabil. 2012 Sep-Oct;33(5):1533-40. doi: 10.1016/j.ridd.2012.03.004. Epub 2012 Apr 21.
• [13] Intronic single nucleotide polymorphisms of engrailed homeobox 2 modulate the disease vulnerability of autism in a han chinese population.Neuropsychobiology. 2010;62(2):104-15. doi: 10.1159/000315441. Epub 2010 Jun 3.
• [14] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [15] A novel protein is lower expressed in renal cell carcinoma.Int J Mol Sci. 2014 Apr 29;15(5):7398-408. doi: 10.3390/ijms15057398.
• [16] Engrailed-2 promoter hyper-methylation is associated with its downregulation in clear cell renal cell carcinoma.Oncol Lett. 2017 Dec;14(6):6888-6894. doi: 10.3892/ol.2017.7000. Epub 2017 Sep 19.
• [17] Haplotype analysis of the engrailed-2 gene in young-onset Parkinson's disease.Neurodegener Dis. 2009;6(3):102-5. doi: 10.1159/000207796. Epub 2009 Mar 6.
• [18] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [19] 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.
• [20] Targeting the beta-catenin/TCF transcriptional complex in the treatment of multiple myeloma. Proc Natl Acad Sci U S A. 2007 May 1;104(18):7516-21. doi: 10.1073/pnas.0610299104. Epub 2007 Apr 23.
• [21] Adaptive changes in global gene expression profile of lung carcinoma A549 cells acutely exposed to distinct types of AhR ligands. Toxicol Lett. 2018 Aug;292:162-174.
• [22] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.