Details of Drug Off-Target (DOT)

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

• DOT Name: Synaptotagmin-7 (SYT7)
• Synonyms: IPCA-7; Prostate cancer-associated protein 7; Synaptotagmin VII; SytVII
• Gene Name: SYT7
• Related Disease:
  Adult glioblastoma
  Bone osteosarcoma
  Colorectal carcinoma
  Glioblastoma multiforme
  Glioma
  Lung cancer
  Lung carcinoma
  Neoplasm
  Non-small-cell lung cancer
  Osteosarcoma
  Prostate cancer
  Prostate carcinoma
  Pulmonary fibrosis
  Hepatocellular carcinoma
  Gastric cancer
  Stomach cancer
• UniProt ID: SYT7_HUMAN
• PDB ID: 2D8K
• Pfam ID: PF00168
• Sequence:
  MYRDPEAASPGAPSRDVLLVSAIITVSLSVTVVLCGLCHWCQRKLGKRYKNSLETVGTPD
  SGRGRSEKKAIKLPAGGKAVNTAPVPGQTPHDESDRRTEPRSSVSDLVNSLTSEMLMLSP
  GSEEDEAHEGCSRENLGRIQFSVGYNFQESTLTVKIMKAQELPAKDFSGTSDPFVKIYLL
  PDKKHKLETKVKRKNLNPHWNETFLFEGFPYEKVVQRILYLQVLDYDRFSRNDPIGEVSI
  PLNKVDLTQMQTFWKDLKPCSDGSGSRGELLLSLCYNPSANSIIVNIIKARNLKAMDIGG
  TSDPYVKVWLMYKDKRVEKKKTVTMKRNLNPIFNESFAFDIPTEKLRETTIIITVMDKDK
  LSRNDVIGKIYLSWKSGPGEVKHWKDMIARPRQPVAQWHQLKA
• Function: Ca(2+) sensor involved in Ca(2+)-dependent exocytosis of secretory and synaptic vesicles through Ca(2+) and phospholipid binding to the C2 domain. Ca(2+) induces binding of the C2-domains to phospholipid membranes and to assembled SNARE-complexes; both actions contribute to triggering exocytosis. SYT7 binds Ca(2+) with high affinity and slow kinetics compared to other synaptotagmins. Involved in Ca(2+)-triggered lysosomal exocytosis, a major component of the plasma membrane repair. Ca(2+)-regulated delivery of lysosomal membranes to the cell surface is also involved in the phagocytic uptake of particles by macrophages. Ca(2+)-triggered lysosomal exocytosis also plays a role in bone remodeling by regulating secretory pathways in osteoclasts and osteoblasts. In case of infection, involved in participates cell invasion by Trypanosoma cruzi via Ca(2+)-triggered lysosomal exocytosis. Involved in cholesterol transport from lysosome to peroxisome by promoting membrane contacts between lysosomes and peroxisomes: probably acts by promoting vesicle fusion by binding phosphatidylinositol-4,5-bisphosphate on peroxisomal membranes. Acts as a key mediator of synaptic facilitation, a process also named short-term synaptic potentiation: synaptic facilitation takes place at synapses with a low initial release probability and is caused by influx of Ca(2+) into the axon terminal after spike generation, increasing the release probability of neurotransmitters. Probably mediates synaptic facilitation by directly increasing the probability of release. May also contribute to synaptic facilitation by regulating synaptic vesicle replenishment, a process required to ensure that synaptic vesicles are ready for the arrival of the next action potential: SYT7 is required for synaptic vesicle replenishment by acting as a sensor for Ca(2+) and by forming a complex with calmodulin. Also acts as a regulator of Ca(2+)-dependent insulin and glucagon secretion in beta-cells. Triggers exocytosis by promoting fusion pore opening and fusion pore expansion in chromaffin cells. Also regulates the secretion of some non-synaptic secretory granules of specialized cells.
• Tissue Specificity: Expressed in a variety of adult and fetal tissues.
• Reactome Pathway: Neurexins and neuroligins (R-HSA-6794361)

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[1]
Bone osteosarcoma	DIST1004	Strong	Biomarker	[2]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[3]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[1]
Glioma	DIS5RPEH	Strong	Biomarker	[1]
Lung cancer	DISCM4YA	Strong	Biomarker	[4]
Lung carcinoma	DISTR26C	Strong	Biomarker	[4]
Neoplasm	DISZKGEW	Strong	Biomarker	[5]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[5]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[2]
Prostate cancer	DISF190Y	Strong	Altered Expression	[1]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[1]
Pulmonary fibrosis	DISQKVLA	Strong	Biomarker	[6]
Hepatocellular carcinoma	DIS0J828	moderate	Altered Expression	[7]
Gastric cancer	DISXGOUK	Limited	Altered Expression	[8]
Stomach cancer	DISKIJSX	Limited	Altered Expression	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Synaptotagmin-7 (SYT7).	[9]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Synaptotagmin-7 (SYT7).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Synaptotagmin-7 (SYT7).	[10]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Synaptotagmin-7 (SYT7).	[11]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Synaptotagmin-7 (SYT7).	[12]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Synaptotagmin-7 (SYT7).	[14]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Synaptotagmin-7 (SYT7).	[15]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Synaptotagmin-7 (SYT7).	[12]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Synaptotagmin-7 (SYT7).	[16]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Synaptotagmin-7 (SYT7).	[17]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Synaptotagmin-7 (SYT7).	[17]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Synaptotagmin-7 (SYT7).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Synaptotagmin-7 (SYT7).	[19]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Synaptotagmin-7 (SYT7).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Synaptotagmin-7 (SYT7).	[21]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Synaptotagmin-7 (SYT7).	[22]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Synaptotagmin-7 (SYT7).	[23]

References

• [1] Downregulation of SYT7 inhibits glioblastoma growth by promoting cellular apoptosis.Mol Med Rep. 2017 Dec;16(6):9017-9022. doi: 10.3892/mmr.2017.7723. Epub 2017 Oct 4.
• [2] Silencing of synaptotagmin 7 regulates osteosarcoma cell proliferation, apoptosis, and migration.Histol Histopathol. 2020 Mar;35(3):303-312. doi: 10.14670/HH-18-174. Epub 2019 Oct 21.
• [3] Synaptotagmin7 Is Overexpressed In Colorectal Cancer And Regulates Colorectal Cancer Cell Proliferation.J Cancer. 2018 Jun 12;9(13):2349-2356. doi: 10.7150/jca.25098. eCollection 2018.
• [4] Synaptotagmin-7, a binding protein of P53, inhibits the senescence and promotes the tumorigenicity of lung cancer cells.Biosci Rep. 2019 Feb 8;39(2):BSR20181298. doi: 10.1042/BSR20181298. Print 2019 Feb 28.
• [5] Synaptotagmin 7 in twist-related protein 1-mediated epithelial - Mesenchymal transition of non-small cell lung cancer.EBioMedicine. 2019 Aug;46:42-53. doi: 10.1016/j.ebiom.2019.07.071. Epub 2019 Aug 6.
• [6] Plexin C1 deficiency permits synaptotagmin 7-mediated macrophage migration and enhances mammalian lung fibrosis.FASEB J. 2016 Dec;30(12):4056-4070. doi: 10.1096/fj.201600373R. Epub 2016 Sep 8.
• [7] Synaptotagmin-7 is overexpressed in hepatocellular carcinoma and regulates hepatocellular carcinoma cell proliferation via Chk1-p53 signaling.Onco Targets Ther. 2017 Aug 29;10:4283-4293. doi: 10.2147/OTT.S143619. eCollection 2017.
• [8] SYT7 acts as a driver of hepatic metastasis formation of gastric cancer cells.Oncogene. 2018 Sep;37(39):5355-5366. doi: 10.1038/s41388-018-0335-8. Epub 2018 Jun 1.
• [9] 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.
• [10] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [11] 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.
• [12] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [13] 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.
• [14] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [15] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [16] 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.
• [17] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [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] 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.
• [20] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [21] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.
• [22] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [23] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.