Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCY3Q2M)

• DOT Name: Protein eva-1 homolog A (EVA1A)
• Synonyms: Protein FAM176A; Transmembrane protein 166
• Gene Name: EVA1A
• Related Disease:
  Acute liver failure
  Adenocarcinoma
  Advanced cancer
  Alzheimer disease
  Cardiac failure
  Cardiomyopathy
  Congestive heart failure
  Glioblastoma multiforme
  Hepatocellular carcinoma
  Huntington disease
  Pancreatic tumour
  Lung cancer
• UniProt ID: EVA1A_HUMAN
• Pfam ID: PF14851
• Sequence:
  MRLPLSHSPEHVEMALLSNILAAYSFVSENPERAALYFVSGVCIGLVLTLAALVIRISCH
  TDCRRRPGKKFLQDRESSSDSSDSEDGSEDTVSDLSVRRHRRFERTLNKNVFTSAEELER
  AQRLEERERIIREIWMNGQPEVPGTRSLNRYY
• Function: Acts as a regulator of programmed cell death, mediating both autophagy and apoptosis.
• Tissue Specificity: Expressed in lung, kidney, liver, pancreas, placenta, but not in heart and skeletal muscle.
• Reactome Pathway:
  Post-translational protein phosphorylation (R-HSA-8957275)
  Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) (R-HSA-381426)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute liver failure	DIS5EZKX	Strong	Biomarker	[1]
Adenocarcinoma	DIS3IHTY	Strong	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[3]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[4]
Cardiac failure	DISDC067	Strong	Biomarker	[5]
Cardiomyopathy	DISUPZRG	Strong	Biomarker	[5]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[5]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[3]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[6]
Huntington disease	DISQPLA4	Strong	Genetic Variation	[4]
Pancreatic tumour	DIS3U0LK	Strong	Altered Expression	[2]
Lung cancer	DISCM4YA	moderate	Altered Expression	[7]

19 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 Protein eva-1 homolog A (EVA1A).	[8]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Protein eva-1 homolog A (EVA1A).	[9]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Protein eva-1 homolog A (EVA1A).	[10]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Protein eva-1 homolog A (EVA1A).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Protein eva-1 homolog A (EVA1A).	[12]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Protein eva-1 homolog A (EVA1A).	[13]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Protein eva-1 homolog A (EVA1A).	[15]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Protein eva-1 homolog A (EVA1A).	[16]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Protein eva-1 homolog A (EVA1A).	[17]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Protein eva-1 homolog A (EVA1A).	[18]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Protein eva-1 homolog A (EVA1A).	[19]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Protein eva-1 homolog A (EVA1A).	[20]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Protein eva-1 homolog A (EVA1A).	[21]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Protein eva-1 homolog A (EVA1A).	[22]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Protein eva-1 homolog A (EVA1A).	[23]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Protein eva-1 homolog A (EVA1A).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Protein eva-1 homolog A (EVA1A).	[26]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Protein eva-1 homolog A (EVA1A).	[27]
QUERCITRIN	DM1DH96	Investigative	QUERCITRIN decreases the expression of Protein eva-1 homolog A (EVA1A).	[28]

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 Protein eva-1 homolog A (EVA1A).	[14]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Protein eva-1 homolog A (EVA1A).	[25]

References

• [1] Liver-specific deletion of Eva1a/Tmem166 aggravates acute liver injury by impairing autophagy.Cell Death Dis. 2018 Jul 10;9(7):768. doi: 10.1038/s41419-018-0800-x.
• [2] Expression profile and potential roles of EVA1A in normal and neoplastic pancreatic tissues.Asian Pac J Cancer Prev. 2015;16(1):373-6. doi: 10.7314/apjcp.2015.16.1.373.
• [3] EVA1A inhibits GBM cell proliferation by inducing autophagy and apoptosis.Exp Cell Res. 2017 Mar 1;352(1):130-138. doi: 10.1016/j.yexcr.2017.02.003. Epub 2017 Feb 6.
• [4] Quantitative proteomics reveals EVA1A-related proteins involved in neuronal differentiation.Proteomics. 2017 Mar;17(5). doi: 10.1002/pmic.201600294. Epub 2017 Feb 21.
• [5] Knockout of Eva1a leads to rapid development of heart failure by impairing autophagy.Cell Death Dis. 2017 Feb 2;8(2):e2586. doi: 10.1038/cddis.2017.17.
• [6] Myc/Max dependent intronic long antisense noncoding RNA, EVA1A-AS, suppresses the expression of Myc/Max dependent anti-proliferating gene EVA1A in a U2 dependent manner.Sci Rep. 2019 Nov 21;9(1):17319. doi: 10.1038/s41598-019-53944-2.
• [7] Adenovirus vector-mediated FAM176A overexpression induces cell death in human H1299 non-small cell lung cancer cells.BMB Rep. 2014 Feb;47(2):104-9. doi: 10.5483/bmbrep.2014.47.2.090.
• [8] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [9] 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.
• [10] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [11] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [12] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [13] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [14] 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.
• [15] 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.
• [16] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [17] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [18] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [19] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [20] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [21] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [22] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [23] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [24] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [25] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [26] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [27] 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.
• [28] Molecular mechanisms of quercitrin-induced apoptosis in non-small cell lung cancer. Arch Med Res. 2014 Aug;45(6):445-54.