Details of Drug Off-Target (DOT)

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

• DOT Name: Augurin (ECRG4)
• Synonyms: Esophageal cancer-related gene 4 protein; ECRG4
• Gene Name: ECRG4
• Related Disease:
  Esophageal squamous cell carcinoma
  Atrial fibrillation
  Aural atresia, congenital
  Colorectal carcinoma
  Ewing sarcoma/peripheral primitive neuroectodermal tumor
  Glioma
  Lung adenocarcinoma
  Malignant glioma
  Nasopharyngeal carcinoma
  Neoplasm
  Neoplasm of esophagus
  Squamous cell carcinoma
  Thyroid gland undifferentiated (anaplastic) carcinoma
  Advanced cancer
  Hepatocellular carcinoma
  Metastatic malignant neoplasm
  Breast cancer
  Breast carcinoma
  Carcinoma of esophagus
  Esophageal cancer
  Thyroid gland papillary carcinoma
• UniProt ID: AUGN_HUMAN
• Pfam ID: PF15187
• Sequence:
  MAASPARPAVLALTGLALLLLLCWGPGGISGNKLKLMLQKREAPVPTKTKVAVDENKAKE
  FLGSLKRQKRQLWDRTRPEVQQWYQQFLYMGFDEAKFEDDITYWLNRDRNGHEYYGDYYQ
  RHYDEDSAIGPRSPYGFRHGASVNYDDY
• Function: Probable hormone that may attenuate cell proliferation and induce senescence of oligodendrocyte and neural precursor cells in the central nervous system. ECRG4-induced senescence is characterized by G1 arrest, RB1 dephosphorylation and accelerated CCND1 and CCND3 proteasomal degradation.
• Tissue Specificity: Expressed in the brain, with expression in the epithelial cell layer of the choroid plexus (at protein level).

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Esophageal squamous cell carcinoma	DIS5N2GV	Definitive	Biomarker	[1]
Atrial fibrillation	DIS15W6U	Strong	Altered Expression	[2]
Aural atresia, congenital	DISCP7UV	Strong	Genetic Variation	[3]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[4]
Ewing sarcoma/peripheral primitive neuroectodermal tumor	DISD4VQC	Strong	Biomarker	[5]
Glioma	DIS5RPEH	Strong	Altered Expression	[6]
Lung adenocarcinoma	DISD51WR	Strong	Altered Expression	[7]
Malignant glioma	DISFXKOV	Strong	Posttranslational Modification	[8]
Nasopharyngeal carcinoma	DISAOTQ0	Strong	Altered Expression	[9]
Neoplasm	DISZKGEW	Strong	Biomarker	[10]
Neoplasm of esophagus	DISOLKAQ	Strong	Altered Expression	[11]
Squamous cell carcinoma	DISQVIFL	Strong	Altered Expression	[12]
Thyroid gland undifferentiated (anaplastic) carcinoma	DISYBB1W	Strong	Biomarker	[13]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[10]
Hepatocellular carcinoma	DIS0J828	moderate	Altered Expression	[14]
Metastatic malignant neoplasm	DIS86UK6	moderate	Biomarker	[15]
Breast cancer	DIS7DPX1	Limited	Posttranslational Modification	[16]
Breast carcinoma	DIS2UE88	Limited	Posttranslational Modification	[16]
Carcinoma of esophagus	DISS6G4D	Limited	Altered Expression	[11]
Esophageal cancer	DISGB2VN	Limited	Altered Expression	[11]
Thyroid gland papillary carcinoma	DIS48YMM	Limited	Genetic Variation	[17]

4 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 Augurin (ECRG4).	[18]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Augurin (ECRG4).	[19]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Augurin (ECRG4).	[20]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Augurin (ECRG4).	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the methylation of Augurin (ECRG4).	[21]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Augurin (ECRG4).	[23]

References

• [1] Expression of ECRG4 is associated with lower proliferative potential of esophageal cancer cells.Pathol Int. 2013 Aug;63(8):391-7. doi: 10.1111/pin.12079.
• [2] A Potential Role of Esophageal Cancer Related Gene-4 for Atrial Fibrillation.Sci Rep. 2017 Jun 2;7(1):2717. doi: 10.1038/s41598-017-02902-x.
• [3] Genome-wide pleiotropy analysis of neuropathological traits related to Alzheimer's disease.Alzheimers Res Ther. 2018 Feb 20;10(1):22. doi: 10.1186/s13195-018-0349-z.
• [4] Genome-wide analysis of aberrant DNA methylation for identification of potential biomarkers in colorectal cancer patients.Asian Pac J Cancer Prev. 2012;13(5):1917-21. doi: 10.7314/apjcp.2012.13.5.1917.
• [5] Potential downstream target genes of aberrant ETS transcription factors are differentially affected in Ewing's sarcoma and prostate carcinoma.PLoS One. 2012;7(11):e49819. doi: 10.1371/journal.pone.0049819. Epub 2012 Nov 19.
• [6] Overexpression of candidate tumor suppressor ECRG4 inhibits glioma proliferation and invasion.J Exp Clin Cancer Res. 2010 Jul 4;29(1):89. doi: 10.1186/1756-9966-29-89.
• [7] Beclin 1 promotes apoptosis and decreases invasion by upregulating the expression of ECRG4 in A549 human lung adenocarcinoma cells.Mol Med Rep. 2016 Jul;14(1):355-60. doi: 10.3892/mmr.2016.5219. Epub 2016 May 6.
• [8] ECRG4 is a candidate tumor suppressor gene frequently hypermethylated in colorectal carcinoma and glioma.BMC Cancer. 2009 Dec 17;9:447. doi: 10.1186/1471-2407-9-447.
• [9] Downregulated ECRG4 is correlated with lymph node metastasis and predicts poor outcome for nasopharyngeal carcinoma patients.Clin Transl Oncol. 2017 Jan;19(1):84-90. doi: 10.1007/s12094-016-1507-z. Epub 2016 Apr 27.
• [10] Serum exosomes contain ECRG4 mRNA that suppresses tumor growth via inhibition of genes involved in inflammation, cell proliferation, and angiogenesis.Cancer Gene Ther. 2018 Oct;25(9-10):248-259. doi: 10.1038/s41417-018-0032-3. Epub 2018 Jul 9.
• [11] Ecrg4 deficiency extends the replicative capacity of neural stem cells in a Foxg1-dependent manner.Development. 2019 Feb 18;146(4):dev168120. doi: 10.1242/dev.168120.
• [12] Expression of ECRG4 is an independent prognostic factor for poor survival in patients with esophageal squamous cell carcinoma.Oncol Rep. 2007 Oct;18(4):981-5.
• [13] Cell Cycle M-Phase Genes Are Highly Upregulated in Anaplastic Thyroid Carcinoma.Thyroid. 2017 Feb;27(2):236-252. doi: 10.1089/thy.2016.0285. Epub 2016 Dec 15.
• [14] Downregulation of esophageal cancer-related gene 4 promotes proliferation and migration of hepatocellular carcinoma.Oncol Lett. 2017 Sep;14(3):3689-3696. doi: 10.3892/ol.2017.6616. Epub 2017 Jul 20.
• [15] Counter regulation of ECRG4 gene expression by hypermethylation-dependent inhibition and the Sp1 transcription factor-dependent stimulation of the c2orf40 promoter.Gene. 2017 Dec 15;636:103-111. doi: 10.1016/j.gene.2017.08.041. Epub 2017 Sep 1.
• [16] ECRG4 acts as a tumor suppressor gene frequently hypermethylated in human breast cancer.Biosci Rep. 2019 May 10;39(5):BSR20190087. doi: 10.1042/BSR20190087. Print 2019 May 31.
• [17] The tumor-promoting function of ECRG4 in papillary thyroid carcinoma and its related mechanism.Tumour Biol. 2015 Feb;36(2):1081-9. doi: 10.1007/s13277-014-2731-1. Epub 2014 Oct 19.
• [18] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [19] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [20] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [21] [Mechanism of loss of human esophageal cancer-related gene 4 (ECRG4) gene expression in esophageal squamous cell carcinoma cell line EC9706]. Zhonghua Zhong Liu Za Zhi. 2011 Aug;33(8):570-3.
• [22] 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.
• [23] 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.