Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTC5F5M6)

• DOT Name: Syntaxin-6 (STX6)
• Gene Name: STX6
• Related Disease:
  Advanced cancer
  Arrhythmia
  Esophageal squamous cell carcinoma
  Myocardial infarction
  Neoplasm
  Prostate cancer
  Prostate carcinoma
  Supranuclear palsy, progressive, 1
  Bacterial infection
  Progressive supranuclear palsy
  Clear cell renal carcinoma
  Renal cell carcinoma
• UniProt ID: STX6_HUMAN
• PDB ID: 2NPS; 4J2C
• Pfam ID: PF05739 ; PF09177
• Sequence:
  MSMEDPFFVVKGEVQKAVNTAQGLFQRWTELLQDPSTATREEIDWTTNELRNNLRSIEWD
  LEDLDETISIVEANPRKFNLDATELSIRKAFITSTRQVVRDMKDQMSTSSVQALAERKNR
  QALLGDSGSQNWSTGTTDKYGRLDRELQRANSHFIEEQQAQQQLIVEQQDEQLELVSGSI
  GVLKNMSQRIGGELEEQAVMLEDFSHELESTQSRLDNVMKKLAKVSHMTSDRRQWCAIAI
  LFAVLLVVLILFLVL
• Function: SNARE promoting movement of transport vesicles to target membranes. Targets endosomes to the trans-Golgi network, and may therefore function in retrograde trafficking. Together with SNARE STX12, promotes movement of vesicles from endosomes to the cell membrane, and may therefore function in the endocytic recycling pathway.
• KEGG Pathway: S.RE interactions in vesicular transport (hsa04130)
• Reactome Pathway:
  Retrograde transport at the Trans-Golgi-Network (R-HSA-6811440)
  Intra-Golgi traffic (R-HSA-6811438)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Arrhythmia	DISFF2NI	Strong	Biomarker	[2]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[3]
Myocardial infarction	DIS655KI	Strong	Biomarker	[2]
Neoplasm	DISZKGEW	Strong	Altered Expression	[3]
Prostate cancer	DISF190Y	Strong	Biomarker	[1]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[1]
Supranuclear palsy, progressive, 1	DIS47BVM	Strong	Biomarker	[4]
Bacterial infection	DIS5QJ9S	moderate	Biomarker	[5]
Progressive supranuclear palsy	DISO5KRQ	moderate	Genetic Variation	[6]
Clear cell renal carcinoma	DISBXRFJ	Limited	Altered Expression	[7]
Renal cell carcinoma	DISQZ2X8	Limited	Altered Expression	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Syntaxin-6 (STX6).	[8]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Syntaxin-6 (STX6).	[16]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Syntaxin-6 (STX6).	[16]

9 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 Syntaxin-6 (STX6).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Syntaxin-6 (STX6).	[10]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Syntaxin-6 (STX6).	[11]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Syntaxin-6 (STX6).	[12]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Syntaxin-6 (STX6).	[13]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Syntaxin-6 (STX6).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Syntaxin-6 (STX6).	[15]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Syntaxin-6 (STX6).	[13]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID increases the expression of Syntaxin-6 (STX6).	[17]

References

• [1] Syntaxin 6-mediated exosome secretion regulates enzalutamide resistance in prostate cancer.Mol Carcinog. 2020 Jan;59(1):62-72. doi: 10.1002/mc.23129. Epub 2019 Nov 1.
• [2] Over-expression of microRNA-1 causes arrhythmia by disturbing intracellular trafficking system.Sci Rep. 2017 Apr 11;7:46259. doi: 10.1038/srep46259.
• [3] Essential role of STX6 in esophageal squamous cell carcinoma growth and migration.Biochem Biophys Res Commun. 2016 Mar 25;472(1):60-7. doi: 10.1016/j.bbrc.2016.02.061. Epub 2016 Feb 22.
• [4] Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy.Nat Genet. 2011 Jun 19;43(7):699-705. doi: 10.1038/ng.859.
• [5] The STX6-VTI1B-VAMP3 complex facilitates xenophagy by regulating the fusion between recycling endosomes and autophagosomes.Autophagy. 2017 Jan 2;13(1):57-69. doi: 10.1080/15548627.2016.1241924. Epub 2016 Oct 28.
• [6] Joint genome-wide association study of progressive supranuclear palsy identifies novel susceptibility loci and genetic correlation to neurodegenerative diseases.Mol Neurodegener. 2018 Aug 8;13(1):41. doi: 10.1186/s13024-018-0270-8.
• [7] Syntaxin 6: A novel predictive and prognostic biomarker in papillary renal cell carcinoma.Sci Rep. 2019 Feb 28;9(1):3146. doi: 10.1038/s41598-019-39305-z.
• [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] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [12] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [13] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [15] 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.
• [16] 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.
• [17] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.