Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4GT1WC)

• DOT Name: Blood vessel epicardial substance (BVES)
• Synonyms: hBVES; Popeye domain-containing protein 1; Popeye protein 1
• Gene Name: BVES
• Related Disease:
  Autosomal recessive limb-girdle muscular dystrophy
  Colitis
  Autosomal recessive limb-girdle muscular dystrophy type 2X
  Cardiac failure
  Colon cancer
  Colon carcinoma
  Congestive heart failure
  Hepatocellular carcinoma
  Ulcerative colitis
  Heart septal defect
  Muscular dystrophy
  Advanced cancer
  Arrhythmia
  Breast cancer
  Breast carcinoma
  Colorectal carcinoma
  Limb-girdle muscular dystrophy
  Neoplasm
  Tetralogy of fallot
• UniProt ID: POPD1_HUMAN
• Pfam ID: PF04831
• Sequence:
  MNYTESSPLRESTAIGFTPELESIIPVPSNKTTCENWREIHHLVFHVANICFAVGLVIPT
  TLHLHMIFLRGMLTLGCTLYIVWATLYRCALDIMIWNSVFLGVNILHLSYLLYKKRPVKI
  EKELSGMYRRLFEPLRVPPDLFRRLTGQFCMIQTLKKGQTYAAEDKTSVDDRLSILLKGK
  MKVSYRGHFLHNIYPCAFIDSPEFRSTQMHKGEKFQVTIIADDNCRFLCWSRERLTYFLE
  SEPFLYEIFRYLIGKDITNKLYSLNDPTLNDKKAKKLEHQLSLCTQISMLEMRNSIASSS
  DSDDGLHQFLRGTSSMSSLHVSSPHQRASAKMKPIEEGAEDDDDVFEPASPNTLKVHQLP
• Function: Cell adhesion molecule involved in the establishment and/or maintenance of cell integrity. Involved in the formation and regulation of the tight junction (TJ) paracellular permeability barrier in epithelial cells. Plays a role in VAMP3-mediated vesicular transport and recycling of different receptor molecules through its interaction with VAMP3. Plays a role in the regulation of cell shape and movement by modulating the Rho-family GTPase activity through its interaction with ARHGEF25/GEFT. Induces primordial adhesive contact and aggregation of epithelial cells in a Ca(2+)-independent manner. Also involved in striated muscle regeneration and repair and in the regulation of cell spreading. Important for the maintenance of cardiac function. Plays a regulatory function in heart rate dynamics mediated, at least in part, through cAMP-binding and, probably, by increasing cell surface expression of the potassium channel KCNK2 and enhancing current density. Is also a caveolae-associated protein important for the preservation of caveolae structural and functional integrity as well as for heart protection against ischemia injury.
• Tissue Specificity: Expressed in epithelial cells (at protein level). Expressed in fetal and adult heart and skeletal muscle.
• KEGG Pathway:
  cAMP sig.ling pathway (hsa04024)
  Adrenergic sig.ling in cardiomyocytes (hsa04261)
  Tight junction (hsa04530)

Molecular Interaction Atlas (MIA) of This DOT

19 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autosomal recessive limb-girdle muscular dystrophy	DISWPGLM	Definitive	Autosomal recessive	[1]
Colitis	DISAF7DD	Definitive	Biomarker	[2]
Autosomal recessive limb-girdle muscular dystrophy type 2X	DISVD9UN	Strong	Autosomal recessive	[3]
Cardiac failure	DISDC067	Strong	Altered Expression	[4]
Colon cancer	DISVC52G	Strong	Biomarker	[5]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[5]
Congestive heart failure	DIS32MEA	Strong	Altered Expression	[4]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[6]
Ulcerative colitis	DIS8K27O	Strong	Altered Expression	[7]
Heart septal defect	DISQ5C5J	moderate	Biomarker	[8]
Muscular dystrophy	DISJD6P7	moderate	Genetic Variation	[3]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[9]
Arrhythmia	DISFF2NI	Limited	Altered Expression	[10]
Breast cancer	DIS7DPX1	Limited	Biomarker	[11]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[11]
Colorectal carcinoma	DIS5PYL0	Limited	Altered Expression	[9]
Limb-girdle muscular dystrophy	DISI9Y1Z	Limited	Biomarker	[3]
Neoplasm	DISZKGEW	Limited	Biomarker	[9]
Tetralogy of fallot	DISMHFNW	Limited	Autosomal recessive	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Blood vessel epicardial substance (BVES).	[13]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Blood vessel epicardial substance (BVES).	[14]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Blood vessel epicardial substance (BVES).	[15]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Blood vessel epicardial substance (BVES).	[16]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Blood vessel epicardial substance (BVES).	[17]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Blood vessel epicardial substance (BVES).	[18]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Blood vessel epicardial substance (BVES).	[19]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Blood vessel epicardial substance (BVES).	[20]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Blood vessel epicardial substance (BVES).	[18]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Blood vessel epicardial substance (BVES).	[22]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Blood vessel epicardial substance (BVES).	[24]

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 increases the methylation of Blood vessel epicardial substance (BVES).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Blood vessel epicardial substance (BVES).	[23]

References

• [1] 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.
• [2] Ten years of research on the role of BVES/ POPDC1 in human disease: a review.Onco Targets Ther. 2019 Feb 18;12:1279-1291. doi: 10.2147/OTT.S192364. eCollection 2019.
• [3] POPDC1(S201F) causes muscular dystrophy and arrhythmia by affecting protein trafficking. J Clin Invest. 2016 Jan;126(1):239-53. doi: 10.1172/JCI79562. Epub 2015 Dec 7.
• [4] Popeye domain-containing 1 is down-regulated in failing human hearts.Int J Mol Med. 2011 Jan;27(1):25-31. doi: 10.3892/ijmm.2010.558. Epub 2010 Nov 10.
• [5] BVES regulates EMT in human corneal and colon cancer cells and is silenced via promoter methylation in human colorectal carcinoma.J Clin Invest. 2011 Oct;121(10):4056-69. doi: 10.1172/JCI44228. Epub 2011 Sep 12.
• [6] MicroRNA-122 triggers mesenchymal-epithelial transition and suppresses hepatocellular carcinoma cell motility and invasion by targeting RhoA.PLoS One. 2014 Jul 3;9(7):e101330. doi: 10.1371/journal.pone.0101330. eCollection 2014.
• [7] BVES is required for maintenance of colonic epithelial integrity in experimental colitis by modifying intestinal permeability.Mucosal Immunol. 2018 Sep;11(5):1363-1374. doi: 10.1038/s41385-018-0043-2. Epub 2018 Jun 15.
• [8] Mutational and functional analysis of the BVES gene coding region in Chinese patients with non-syndromic tetralogy of Fallot.Int J Mol Med. 2013 Apr;31(4):899-903. doi: 10.3892/ijmm.2013.1275. Epub 2013 Feb 7.
• [9] Blood vessel epicardial substance reduces LRP6 receptor and cytoplasmic -catenin levels to modulate Wnt signaling and intestinal homeostasis.Carcinogenesis. 2019 Sep 18;40(9):1086-1098. doi: 10.1093/carcin/bgz007.
• [10] The Popeye domain containing gene family encoding a family of cAMP-effector proteins with important functions in striated muscle and beyond.J Muscle Res Cell Motil. 2019 Jun;40(2):169-183. doi: 10.1007/s10974-019-09523-z. Epub 2019 Jun 13.
• [11] Dysregulation of POPDC1 promotes breast cancer cell migration and proliferation.Biosci Rep. 2017 Nov 21;37(6):BSR20171039. doi: 10.1042/BSR20171039. Print 2017 Dec 22.
• [12] 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.
• [13] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [14] 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.
• [15] 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.
• [16] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [17] Gene expression profile induced by arsenic trioxide in chronic lymphocytic leukemia cells reveals a central role for heme oxygenase-1 in apoptosis and regulation of matrix metalloproteinase-9. Oncotarget. 2016 Dec 13;7(50):83359-83377.
• [18] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [19] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [20] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [21] 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.
• [22] BET bromodomain inhibition targets both c-Myc and IL7R in high-risk acute lymphoblastic leukemia. Blood. 2012 Oct 4;120(14):2843-52.
• [23] 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.
• [24] 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.