Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7US3NO)

• DOT Name: Beta-galactoside alpha-2,6-sialyltransferase 1 (ST6GAL1)
• Synonyms: Alpha 2,6-ST 1; EC 2.4.3.1; B-cell antigen CD75; CMP-N-acetylneuraminate-beta-galactosamide-alpha-2,6-sialyltransferase 1; ST6Gal I; ST6GalI; Sialyltransferase 1
• Gene Name: ST6GAL1
• Related Disease:
  Asthma
  Colon cancer
  Adenocarcinoma
  Adult glioblastoma
  Advanced cancer
  Allergic contact dermatitis
  Alzheimer disease
  Arteriosclerosis
  Atherosclerosis
  Bladder cancer
  Breast cancer
  Carcinoma
  Cervical cancer
  Cervical carcinoma
  Colorectal carcinoma
  Epithelial ovarian cancer
  Glioblastoma multiforme
  Glioma
  Hepatocellular carcinoma
  Liver cancer
  Lung cancer
  Lung carcinoma
  Malignant glioma
  Matthew-Wood syndrome
  Neoplasm
  Non-small-cell lung cancer
  Obesity
  Ovarian cancer
  Ovarian neoplasm
  Pancreatic cancer
  Prostate cancer
  Prostate carcinoma
  Rheumatoid arthritis
  Squamous cell carcinoma
  T-cell acute lymphoblastic leukaemia
  Triple negative breast cancer
  Type-1/2 diabetes
  Urinary bladder cancer
  Urinary bladder neoplasm
  Gastric cancer
  Metastatic malignant neoplasm
  Stomach cancer
  Breast carcinoma
  Colon carcinoma
  Coronary heart disease
  IgA nephropathy
  Neoplasm of esophagus
  Non-insulin dependent diabetes
• UniProt ID: SIAT1_HUMAN
• PDB ID: 4JS1; 4JS2; 6QVS; 6QVT
• EC Number: 2.4.3.1
• Pfam ID: PF00777
• Sequence:
  MIHTNLKKKFSCCVLVFLLFAVICVWKEKKKGSYYDSFKLQTKEFQVLKSLGKLAMGSDS
  QSVSSSSTQDPHRGRQTLGSLRGLAKAKPEASFQVWNKDSSSKNLIPRLQKIWKNYLSMN
  KYKVSYKGPGPGIKFSAEALRCHLRDHVNVSMVEVTDFPFNTSEWEGYLPKESIRTKAGP
  WGRCAVVSSAGSLKSSQLGREIDDHDAVLRFNGAPTANFQQDVGTKTTIRLMNSQLVTTE
  KRFLKDSLYNEGILIVWDPSVYHSDIPKWYQNPDYNFFNNYKTYRKLHPNQPFYILKPQM
  PWELWDILQEISPEEIQPNPPSSGMLGIIIMMTLCDQVDIYEFLPSKRKTDVCYYYQKFF
  DSACTMGAYHPLLYEKNLVKHLNQGTDEDIYLLGKATLPGFRTIHC
• Function: Transfers sialic acid from CMP-sialic acid to galactose-containing acceptor substrates.
• KEGG Pathway:
  N-Glycan biosynthesis (hsa00510)
  Other types of O-glycan biosynthesis (hsa00514)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Maturation of protein 3a (R-HSA-9683673)
  Maturation of spike protein (R-HSA-9694548)
  Maturation of protein 3a (R-HSA-9694719)
  N-Glycan antennae elongation (R-HSA-975577)
  Termination of O-glycan biosynthesis (R-HSA-977068)
  Sialic acid metabolism (R-HSA-4085001)
• BioCyc Pathway: MetaCyc:HS01118-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

48 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Asthma	DISW9QNS	Definitive	Biomarker	[1]
Colon cancer	DISVC52G	Definitive	Biomarker	[2]
Adenocarcinoma	DIS3IHTY	Strong	Biomarker	[3]
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[4]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[5]
Allergic contact dermatitis	DISFFVF9	Strong	Biomarker	[6]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[7]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[8]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[8]
Bladder cancer	DISUHNM0	Strong	Altered Expression	[9]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[10]
Carcinoma	DISH9F1N	Strong	Altered Expression	[11]
Cervical cancer	DISFSHPF	Strong	Biomarker	[12]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[12]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[13]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[14]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[4]
Glioma	DIS5RPEH	Strong	Altered Expression	[4]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[15]
Liver cancer	DISDE4BI	Strong	Altered Expression	[16]
Lung cancer	DISCM4YA	Strong	Genetic Variation	[17]
Lung carcinoma	DISTR26C	Strong	Genetic Variation	[17]
Malignant glioma	DISFXKOV	Strong	Altered Expression	[18]
Matthew-Wood syndrome	DISA7HR7	Strong	Biomarker	[19]
Neoplasm	DISZKGEW	Strong	Biomarker	[15]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[16]
Obesity	DIS47Y1K	Strong	Genetic Variation	[20]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[14]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[14]
Pancreatic cancer	DISJC981	Strong	Biomarker	[21]
Prostate cancer	DISF190Y	Strong	Biomarker	[22]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[22]
Rheumatoid arthritis	DISTSB4J	Strong	Biomarker	[23]
Squamous cell carcinoma	DISQVIFL	Strong	Genetic Variation	[24]
T-cell acute lymphoblastic leukaemia	DIS17AI2	Strong	Biomarker	[25]
Triple negative breast cancer	DISAMG6N	Strong	Altered Expression	[26]
Type-1/2 diabetes	DISIUHAP	Strong	Biomarker	[27]
Urinary bladder cancer	DISDV4T7	Strong	Altered Expression	[9]
Urinary bladder neoplasm	DIS7HACE	Strong	Altered Expression	[9]
Gastric cancer	DISXGOUK	moderate	Biomarker	[28]
Metastatic malignant neoplasm	DIS86UK6	moderate	Biomarker	[12]
Stomach cancer	DISKIJSX	moderate	Biomarker	[28]
Breast carcinoma	DIS2UE88	Limited	Altered Expression	[16]
Colon carcinoma	DISJYKUO	Limited	Altered Expression	[16]
Coronary heart disease	DIS5OIP1	Limited	Biomarker	[29]
IgA nephropathy	DISZ8MTK	Limited	Genetic Variation	[30]
Neoplasm of esophagus	DISOLKAQ	Limited	Genetic Variation	[24]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Genetic Variation	[31]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Flucloxacillin	DMNUWST	Approved	Beta-galactoside alpha-2,6-sialyltransferase 1 (ST6GAL1) increases the Liver injury ADR of Flucloxacillin.	[50]

18 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 Beta-galactoside alpha-2,6-sialyltransferase 1 (ST6GAL1).	[32]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Beta-galactoside alpha-2,6-sialyltransferase 1 (ST6GAL1).	[33]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Beta-galactoside alpha-2,6-sialyltransferase 1 (ST6GAL1).	[34]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Beta-galactoside alpha-2,6-sialyltransferase 1 (ST6GAL1).	[35]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Beta-galactoside alpha-2,6-sialyltransferase 1 (ST6GAL1).	[36]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Beta-galactoside alpha-2,6-sialyltransferase 1 (ST6GAL1).	[33]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Beta-galactoside alpha-2,6-sialyltransferase 1 (ST6GAL1).	[37]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Beta-galactoside alpha-2,6-sialyltransferase 1 (ST6GAL1).	[38]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Beta-galactoside alpha-2,6-sialyltransferase 1 (ST6GAL1).	[39]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Beta-galactoside alpha-2,6-sialyltransferase 1 (ST6GAL1).	[40]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Beta-galactoside alpha-2,6-sialyltransferase 1 (ST6GAL1).	[41]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Beta-galactoside alpha-2,6-sialyltransferase 1 (ST6GAL1).	[42]
DTI-015	DMXZRW0	Approved	DTI-015 increases the expression of Beta-galactoside alpha-2,6-sialyltransferase 1 (ST6GAL1).	[43]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Beta-galactoside alpha-2,6-sialyltransferase 1 (ST6GAL1).	[44]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Beta-galactoside alpha-2,6-sialyltransferase 1 (ST6GAL1).	[46]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Beta-galactoside alpha-2,6-sialyltransferase 1 (ST6GAL1).	[47]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride increases the expression of Beta-galactoside alpha-2,6-sialyltransferase 1 (ST6GAL1).	[48]
	DM9CEI5		decreases the activity of Beta-galactoside alpha-2,6-sialyltransferase 1 (ST6GAL1).	[49]

1 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 decreases the methylation of Beta-galactoside alpha-2,6-sialyltransferase 1 (ST6GAL1).	[45]

References

• [1] Sialylation of MUC4 N-glycans by ST6GAL1 orchestrates human airway epithelial cell differentiation associated with type-2 inflammation.JCI Insight. 2019 Mar 7;4(5):e122475. doi: 10.1172/jci.insight.122475. eCollection 2019 Mar 7.
• [2] Sialylation of epidermal growth factor receptor regulates receptor activity and chemosensitivity to gefitinib in colon cancer cells.Biochem Pharmacol. 2012 Apr 1;83(7):849-57. doi: 10.1016/j.bcp.2012.01.007. Epub 2012 Jan 13.
• [3] Sox2 promotes expression of the ST6Gal-I glycosyltransferase in ovarian cancer cells.J Ovarian Res. 2019 Oct 14;12(1):93. doi: 10.1186/s13048-019-0574-5.
• [4] The role of DNA methylation in ST6Gal1 expression in gliomas.Glycobiology. 2016 Dec;26(12):1271-1283. doi: 10.1093/glycob/cww058. Epub 2016 Aug 10.
• [5] B cells suppress medullary granulopoiesis by an extracellular glycosylation-dependent mechanism.Elife. 2019 Aug 13;8:e47328. doi: 10.7554/eLife.47328.
• [6] Gene transcripts as potential diagnostic markers for allergic contact dermatitis.Contact Dermatitis. 2005 Aug;53(2):100-6. doi: 10.1111/j.0105-1873.2005.00658.x.
• [7] Disrupted glycosylation of lipids and proteins is a cause of neurodegeneration.Brain. 2020 May 1;143(5):1332-1340. doi: 10.1093/brain/awz358.
• [8] ST6GAL1 negatively regulates monocyte transendothelial migration and atherosclerosis development.Biochem Biophys Res Commun. 2018 Jun 2;500(2):249-255. doi: 10.1016/j.bbrc.2018.04.053. Epub 2018 Apr 16.
• [9] Epigenetic inactivation of ST6GAL1 in human bladder cancer.BMC Cancer. 2014 Dec 2;14:901. doi: 10.1186/1471-2407-14-901.
• [10] Triple-negative and HER2-overexpressing breast cancer cell sialylation impacts tumor microenvironment T-lymphocyte subset recruitment: a possible mechanism of tumor escape.Cancer Manag Res. 2018 May 4;10:1051-1059. doi: 10.2147/CMAR.S162932. eCollection 2018.
• [11] -Galactoside 2,6-sialyltranferase 1 promotes transforming growth factor--mediated epithelial-mesenchymal transition.J Biol Chem. 2014 Dec 12;289(50):34627-41. doi: 10.1074/jbc.M114.593392. Epub 2014 Oct 24.
• [12] Knockdown of ST6Gal-I increases cisplatin sensitivity in cervical cancer cells.BMC Cancer. 2016 Dec 16;16(1):949. doi: 10.1186/s12885-016-2981-y.
• [13] The HOTAIR/miR-214/ST6GAL1 crosstalk modulates colorectal cancer procession through mediating sialylated c-Met via JAK2/STAT3 cascade.J Exp Clin Cancer Res. 2019 Nov 6;38(1):455. doi: 10.1186/s13046-019-1468-5.
• [14] Prognostic role of the sialyltransferase ST6GAL1 in ovarian cancer.Glycobiology. 2018 Nov 1;28(11):898-903. doi: 10.1093/glycob/cwy065.
• [15] 2,6-Sialylation promotes immune escape in hepatocarcinoma cells by regulating T cell functions and CD147/MMP signaling.J Physiol Biochem. 2019 Jun;75(2):199-207. doi: 10.1007/s13105-019-00674-8. Epub 2019 Apr 10.
• [16] Modification of 2,6-sialylation mediates the invasiveness and tumorigenicity of non-small cell lung cancer cells in vitro and in vivo via Notch1/Hes1/MMPs pathway.Int J Cancer. 2018 Nov 1;143(9):2319-2330. doi: 10.1002/ijc.31737. Epub 2018 Sep 7.
• [17] Influences of two significant variants located in the ST6GAL1 3'-untranslated region on lung carcinoma susceptibility in the Chinese Han population.Eur J Cancer Prev. 2020 Jan;29(1):60-64. doi: 10.1097/CEJ.0000000000000512.
• [18] Alpha2,6-sialylation of cell-surface N-glycans inhibits glioma formation in vivo.Cancer Res. 2001 Sep 15;61(18):6822-9.
• [19] ST6Gal-I sialyltransferase promotes chemoresistance in pancreatic ductal adenocarcinoma by abrogating gemcitabine-mediated DNA damage.J Biol Chem. 2018 Jan 19;293(3):984-994. doi: 10.1074/jbc.M117.808584. Epub 2017 Nov 30.
• [20] Effect of six type II diabetes susceptibility loci and an FTO variant on obesity in Pakistani subjects.Eur J Hum Genet. 2016 Jun;24(6):903-10. doi: 10.1038/ejhg.2015.212. Epub 2015 Sep 23.
• [21] Elevation of -galactoside 2,6-sialyltransferase 1 in a fructoseresponsive manner promotes pancreatic cancer metastasis.Oncotarget. 2017 Jan 31;8(5):7691-7709. doi: 10.18632/oncotarget.13845.
• [22] Sialyltransferase-Based Chemoenzymatic Histology for the Detection of N- and O-Glycans.Bioconjug Chem. 2018 Apr 18;29(4):1231-1239. doi: 10.1021/acs.bioconjchem.8b00021. Epub 2018 Mar 23.
• [23] -2,3-Sialyltransferase 1 and neuraminidase-3 from monocytes in patients with rheumatoid arthritis correlate with disease activity measures: A pilot study.J Chin Med Assoc. 2019 Mar;82(3):179-185. doi: 10.1097/JCMA.0000000000000027.
• [24] Genome-wide association analyses of esophageal squamous cell carcinoma in Chinese identify multiple susceptibility loci and gene-environment interactions.Nat Genet. 2012 Oct;44(10):1090-7. doi: 10.1038/ng.2411. Epub 2012 Sep 9.
• [25] Correction to: The regulatory ZFAS1/miR-150/ST6GAL1 crosstalk modulates sialylation of EGFR via PI3K/Akt pathway in T-cell acute lymphoblastic leukemia.J Exp Clin Cancer Res. 2019 Aug 16;38(1):357. doi: 10.1186/s13046-019-1365-y.
• [26] MiR-214-3p regulates the viability, invasion, migration and EMT of TNBC cells by targeting ST6GAL1.Cytotechnology. 2019 Dec;71(6):1155-1165. doi: 10.1007/s10616-019-00352-z. Epub 2019 Nov 8.
• [27] Identification of PTPN22, ST6GAL1 and JAZF1 as psoriasis risk genes demonstrates shared pathogenesis between psoriasis and diabetes.Exp Dermatol. 2017 Nov;26(11):1112-1117. doi: 10.1111/exd.13393. Epub 2017 Aug 25.
• [28] Increasing HER2 2,6 sialylation facilitates gastric cancer progression and resistance via the Akt and ERK pathways.Oncol Rep. 2018 Nov;40(5):2997-3005. doi: 10.3892/or.2018.6680. Epub 2018 Aug 31.
• [29] Large scale association analysis identifies three susceptibility loci for coronary artery disease.PLoS One. 2011;6(12):e29427. doi: 10.1371/journal.pone.0029427. Epub 2011 Dec 27.
• [30] Identification of new susceptibility loci for IgA nephropathy in Han Chinese.Nat Commun. 2015 Jun 1;6:7270. doi: 10.1038/ncomms8270.
• [31] Identification of 28 new susceptibility loci for type 2 diabetes in the Japanese population.Nat Genet. 2019 Mar;51(3):379-386. doi: 10.1038/s41588-018-0332-4. Epub 2019 Feb 4.
• [32] 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.
• [33] 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.
• [34] 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.
• [35] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [36] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [37] 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.
• [38] 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.
• [39] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [40] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [41] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [42] 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.
• [43] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [44] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [45] 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.
• [46] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.
• [47] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [48] The contact allergen nickel triggers a unique inflammatory and proangiogenic gene expression pattern via activation of NF-kappaB and hypoxia-inducible factor-1alpha. J Immunol. 2007 Mar 1;178(5):3198-207.
• [49] A novel sialyltransferase inhibitor suppresses FAK/paxillin signaling and cancer angiogenesis and metastasis pathways. Cancer Res. 2011 Jan 15;71(2):473-83. doi: 10.1158/0008-5472.CAN-10-1303. Epub 2011 Jan 11.
• [50] HLA-B*5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin. Nat Genet. 2009 Jul;41(7):816-9. doi: 10.1038/ng.379. Epub 2009 May 31.