Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0V8OYK)

• DOT Name: Homeobox protein EMX2 (EMX2)
• Synonyms: Empty spiracles homolog 2; Empty spiracles-like protein 2
• Gene Name: EMX2
• Related Disease:
  Isolated congenital microcephaly
  Nervous system disease
  Thyroid gland papillary carcinoma
  Adult glioblastoma
  Colorectal carcinoma
  Disorder of sexual differentiation
  Endometriosis
  Esophageal adenocarcinoma
  Familial multiple trichoepithelioma
  Gastric cancer
  Glioblastoma multiforme
  Glioma
  Hypospadias
  Kallmann syndrome
  Lung cancer
  Lung carcinoma
  Lung neoplasm
  Neoplasm
  Stomach cancer
  Vesicoureteral reflux
  46,XY disorder of sex development
  Plasma cell myeloma
  Schizencephaly
  Squamous cell carcinoma
  Adenocarcinoma
  Colorectal adenocarcinoma
  Colorectal neoplasm
  Lung adenocarcinoma
  Malignant pleural mesothelioma
  Minimally invasive lung adenocarcinoma
• UniProt ID: EMX2_HUMAN
• Pfam ID: PF00046
• Sequence:
  MFQPAPKRCFTIESLVAKDSPLPASRSEDPIRPAALSYANSSPINPFLNGFHSAAAAAAG
  RGVYSNPDLVFAEAVSHPPNPAVPVHPVPPPHALAAHPLPSSHSPHPLFASQQRDPSTFY
  PWLIHRYRYLGHRFQGNDTSPESFLLHNALARKPKRIRTAFSPSQLLRLEHAFEKNHYVV
  GAERKQLAHSLSLTETQVKVWFQNRRTKFKRQKLEEEGSDSQQKKKGTHHINRWRIATKQ
  ASPEEIDVTSDD
• Function: Transcription factor, which in cooperation with EMX1, acts to generate the boundary between the roof and archipallium in the developing brain. May function in combination with OTX1/2 to specify cell fates in the developing central nervous system.
• Tissue Specificity: Cerebral cortex.

Molecular Interaction Atlas (MIA) of This DOT

30 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Isolated congenital microcephaly	DISUXHZ6	Definitive	Genetic Variation	[1]
Nervous system disease	DISJ7GGT	Definitive	Altered Expression	[2]
Thyroid gland papillary carcinoma	DIS48YMM	Definitive	Biomarker	[3]
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[4]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[5]
Disorder of sexual differentiation	DISRMAEZ	Strong	Genetic Variation	[6]
Endometriosis	DISX1AG8	Strong	Genetic Variation	[7]
Esophageal adenocarcinoma	DISODWFP	Strong	Biomarker	[8]
Familial multiple trichoepithelioma	DISKZAUY	Strong	Altered Expression	[8]
Gastric cancer	DISXGOUK	Strong	Biomarker	[9]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[4]
Glioma	DIS5RPEH	Strong	Altered Expression	[10]
Hypospadias	DIS48CCP	Strong	Genetic Variation	[6]
Kallmann syndrome	DISO3HDG	Strong	Genetic Variation	[11]
Lung cancer	DISCM4YA	Strong	Biomarker	[12]
Lung carcinoma	DISTR26C	Strong	Biomarker	[12]
Lung neoplasm	DISVARNB	Strong	Biomarker	[12]
Neoplasm	DISZKGEW	Strong	Biomarker	[13]
Stomach cancer	DISKIJSX	Strong	Biomarker	[9]
Vesicoureteral reflux	DISUL6SA	Strong	Biomarker	[14]
46,XY disorder of sex development	DIS78CGG	moderate	Altered Expression	[15]
Plasma cell myeloma	DIS0DFZ0	moderate	Biomarker	[16]
Schizencephaly	DISZVYEC	Moderate	Autosomal dominant	[17]
Squamous cell carcinoma	DISQVIFL	moderate	Altered Expression	[18]
Adenocarcinoma	DIS3IHTY	Limited	Altered Expression	[19]
Colorectal adenocarcinoma	DISPQOUB	Limited	Altered Expression	[20]
Colorectal neoplasm	DISR1UCN	Limited	Altered Expression	[20]
Lung adenocarcinoma	DISD51WR	Limited	Altered Expression	[19]
Malignant pleural mesothelioma	DIST2R60	Limited	Altered Expression	[21]
Minimally invasive lung adenocarcinoma	DIS4W83X	Limited	Biomarker	[19]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Homeobox protein EMX2 (EMX2) increases the response to substance of Cisplatin.	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Homeobox protein EMX2 (EMX2).	[22]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Homeobox protein EMX2 (EMX2).	[23]
Amphotericin B	DMTAJQE	Approved	Amphotericin B decreases the expression of Homeobox protein EMX2 (EMX2).	[24]
Melphalan	DMOLNHF	Approved	Melphalan decreases the expression of Homeobox protein EMX2 (EMX2).	[25]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Homeobox protein EMX2 (EMX2).	[26]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Homeobox protein EMX2 (EMX2).	[29]

2 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 EMX2 (EMX2).	[27]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Homeobox protein EMX2 (EMX2).	[28]

References

• [1] A missense mutation in SNRPE linked to non-syndromal microcephaly interferes with U snRNP assembly and pre-mRNA splicing.PLoS Genet. 2019 Oct 31;15(10):e1008460. doi: 10.1371/journal.pgen.1008460. eCollection 2019 Oct.
• [2] Enhancing Neuronogenesis and Counteracting Neuropathogenic Gene Haploinsufficiencies by RNA Gene Activation.Adv Exp Med Biol. 2017;983:23-39. doi: 10.1007/978-981-10-4310-9_2.
• [3] The downregulation of lncRNA EMX2OS might independently predict shorter recurrence-free survival of classical papillary thyroid cancer.PLoS One. 2018 Dec 21;13(12):e0209338. doi: 10.1371/journal.pone.0209338. eCollection 2018.
• [4] The expression of EMX2 lead to cell cycle arrest in glioblastoma cell line.BMC Cancer. 2018 Dec 4;18(1):1213. doi: 10.1186/s12885-018-5094-y.
• [5] Empty Spiracles Homeobox 2 (EMX2) Inhibits the Invasion and Tumorigenesis in Colorectal Cancer Cells.Oncol Res. 2017 Apr 14;25(4):537-544. doi: 10.3727/096504016X14756640150695. Epub 2016 Oct 5.
• [6] Severe sex differentiation disorder in a boy with a 3.8 Mb 10q25.3-q26.12 microdeletion encompassing EMX2.Am J Med Genet A. 2014 Oct;164A(10):2618-22. doi: 10.1002/ajmg.a.36662. Epub 2014 Jun 26.
• [7] Variants in EMX2 and PTEN do not contribute to risk of endometriosis.Mol Hum Reprod. 2007 Aug;13(8):587-94. doi: 10.1093/molehr/gam023. Epub 2007 Jun 11.
• [8] EMX2 is epigenetically silenced and suppresses epithelialmesenchymal transition in human esophageal adenocarcinoma.Oncol Rep. 2019 Nov;42(5):2169-2178. doi: 10.3892/or.2019.7284. Epub 2019 Aug 20.
• [9] Adenoviral delivery of the EMX2 gene suppresses growth in human gastric cancer.PLoS One. 2012;7(9):e45970. doi: 10.1371/journal.pone.0045970. Epub 2012 Sep 21.
• [10] Redistribution of EZH2 promotes malignant phenotypes by rewiring developmental programmes.EMBO Rep. 2019 Oct 4;20(10):e48155. doi: 10.15252/embr.201948155. Epub 2019 Aug 29.
• [11] Mutation analysis of the EMX2 gene in Kallmann's syndrome.Fertil Steril. 1999 Nov;72(5):910-4. doi: 10.1016/s0015-0282(99)00376-3.
• [12] EMX2 is epigenetically silenced and suppresses growth in human lung cancer. Oncogene. 2010 Nov 4;29(44):5969-75. doi: 10.1038/onc.2010.330. Epub 2010 Aug 9.
• [13] Emx2 as a novel tool to suppress glioblastoma.Oncotarget. 2016 Jul 5;7(27):41005-41016. doi: 10.18632/oncotarget.9322.
• [14] Vesicoureteral reflux and other urinary tract malformations in mice compound heterozygous for Pax2 and Emx2.PLoS One. 2011;6(6):e21529. doi: 10.1371/journal.pone.0021529. Epub 2011 Jun 24.
• [15] Assembling the jigsaw puzzle: CBX2 isoform 2 and its targets in disorders/differences of sex development.Mol Genet Genomic Med. 2018 Sep;6(5):785-795. doi: 10.1002/mgg3.445. Epub 2018 Jul 11.
• [16] Wnt and BMP signaling pathways co-operatively induce the differentiation of multiple myeloma mesenchymal stem cells into osteoblasts by upregulating EMX2.J Cell Biochem. 2019 Apr;120(4):6515-6527. doi: 10.1002/jcb.27942. Epub 2018 Nov 18.
• [17] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [18] EMX2 Is a Predictive Marker for Adjuvant Chemotherapy in Lung Squamous Cell Carcinomas.PLoS One. 2015 Jul 1;10(7):e0132134. doi: 10.1371/journal.pone.0132134. eCollection 2015.
• [19] Downregulation of EMX2 is associated with clinical outcomes in lung adenocarcinoma patients.Clin Lung Cancer. 2011 Jul;12(4):237-44. doi: 10.1016/j.cllc.2011.03.025. Epub 2011 Apr 24.
• [20] EMX2 gene expression predicts liver metastasis and survival in colorectal cancer.BMC Cancer. 2017 Aug 22;17(1):555. doi: 10.1186/s12885-017-3556-2.
• [21] The homeobox gene EMX2 is a prognostic and predictive marker in malignant pleural mesothelioma.Lung Cancer. 2014 Sep;85(3):465-71. doi: 10.1016/j.lungcan.2014.06.018. Epub 2014 Jun 30.
• [22] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [23] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [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] Bone marrow osteoblast damage by chemotherapeutic agents. PLoS One. 2012;7(2):e30758. doi: 10.1371/journal.pone.0030758. Epub 2012 Feb 17.
• [26] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [27] 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.
• [28] 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.
• [29] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [30] EMX2 is epigenetically silenced and suppresses growth in human lung cancer. Oncogene. 2010 Nov 4;29(44):5969-75. doi: 10.1038/onc.2010.330. Epub 2010 Aug 9.