Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTF6OC66)

• DOT Name: Beta-1,3-galactosyl-O-glycosyl-glycoprotein beta-1,6-N-acetylglucosaminyltransferase (GCNT1)
• Synonyms: EC 2.4.1.102; Core 2 beta-1,6-N-acetylglucosaminyltransferase; C2GlcNAcT; Core 2-branching enzyme; Core2-GlcNAc-transferase; C2GNT; Core 2 GNT; Leukocyte type core 2 beta-1,6-N-acetylglucosaminyltransferase; C2GnT-L
• Gene Name: GCNT1
• Related Disease:
  Prostate carcinoma
  Advanced cancer
  Lung cancer
  Lung carcinoma
  Pancreatic cancer
  Testicular germ cell tumor
  Carcinoma
  Adenocarcinoma
  Colorectal carcinoma
  Diphtheria
  Neuroblastoma
  Prostate cancer
  Prostate neoplasm
• UniProt ID: GCNT1_HUMAN
• EC Number: 2.4.1.102
• Pfam ID: PF02485
• Sequence:
  MLRTLLRRRLFSYPTKYYFMVLVLSLITFSVLRIHQKPEFVSVRHLELAGENPSSDINCT
  KVLQGDVNEIQKVKLEILTVKFKKRPRWTPDDYINMTSDCSSFIKRRKYIVEPLSKEEAE
  FPIAYSIVVHHKIEMLDRLLRAIYMPQNFYCIHVDTKSEDSYLAAVMGIASCFSNVFVAS
  RLESVVYASWSRVQADLNCMKDLYAMSANWKYLINLCGMDFPIKTNLEIVRKLKLLMGEN
  NLETERMPSHKEERWKKRYEVVNGKLTNTGTVKMLPPLETPLFSGSAYFVVSREYVGYVL
  QNEKIQKLMEWAQDTYSPDEYLWATIQRIPEVPGSLPASHKYDLSDMQAVARFVKWQYFE
  GDVSKGAPYPPCDGVHVRSVCIFGAGDLNWMLRKHHLFANKFDVDVDLFAIQCLDEHLRH
  KALETLKH
• Function: Glycosyltransferase that catalyzes the transfer of an N-acetylglucosamine (GlcNAc) moiety in beta1-6 linkage from UDP-GlcNAc onto mucin-type core 1 O-glycan to form the branched mucin-type core 2 O-glycan. The catalysis is metal ion-independent and occurs with inversion of the anomeric configuration of sugar donor. Selectively involved in synthesis of mucin-type core 2 O-glycans that serve as scaffolds for the display of selectin ligand sialyl Lewis X epitope by myeloid cells, with an impact on homeostasis and recruitment to inflammatory sites. Can also act on glycolipid substrates. Transfers GlcNAc moiety to GalGb4Cer globosides in a reaction step to the synthesis of stage-specific embryonic antigen 1 (SSEA-1) determinant. Can use Galbeta1-3GalNAcalpha1- and Galbeta1-3GalNAcbeta1- oligosaccharide derivatives as acceptor substrates.
• Tissue Specificity: Highly expressed in activated T-lymphocytes and myeloid cells.
• KEGG Pathway:
  Mucin type O-glycan biosynthesis (hsa00512)
  Metabolic pathways (hsa01100)
• Reactome Pathway: O-linked glycosylation of mucins (R-HSA-913709)
• BioCyc Pathway: MetaCyc:HS05939-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Prostate carcinoma	DISMJPLE	Definitive	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[2]
Lung cancer	DISCM4YA	Strong	Altered Expression	[3]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[3]
Pancreatic cancer	DISJC981	Strong	Biomarker	[4]
Testicular germ cell tumor	DIS5RN24	Strong	Biomarker	[5]
Carcinoma	DISH9F1N	moderate	Altered Expression	[6]
Adenocarcinoma	DIS3IHTY	Disputed	Altered Expression	[7]
Colorectal carcinoma	DIS5PYL0	Limited	Altered Expression	[8]
Diphtheria	DISZWM55	Limited	Altered Expression	[9]
Neuroblastoma	DISVZBI4	Limited	Altered Expression	[10]
Prostate cancer	DISF190Y	Limited	Altered Expression	[1]
Prostate neoplasm	DISHDKGQ	Limited	Biomarker	[11]

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-1,3-galactosyl-O-glycosyl-glycoprotein beta-1,6-N-acetylglucosaminyltransferase (GCNT1).	[12]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Beta-1,3-galactosyl-O-glycosyl-glycoprotein beta-1,6-N-acetylglucosaminyltransferase (GCNT1).	[13]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Beta-1,3-galactosyl-O-glycosyl-glycoprotein beta-1,6-N-acetylglucosaminyltransferase (GCNT1).	[14]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Beta-1,3-galactosyl-O-glycosyl-glycoprotein beta-1,6-N-acetylglucosaminyltransferase (GCNT1).	[15]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Beta-1,3-galactosyl-O-glycosyl-glycoprotein beta-1,6-N-acetylglucosaminyltransferase (GCNT1).	[16]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Beta-1,3-galactosyl-O-glycosyl-glycoprotein beta-1,6-N-acetylglucosaminyltransferase (GCNT1).	[17]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Beta-1,3-galactosyl-O-glycosyl-glycoprotein beta-1,6-N-acetylglucosaminyltransferase (GCNT1).	[18]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Beta-1,3-galactosyl-O-glycosyl-glycoprotein beta-1,6-N-acetylglucosaminyltransferase (GCNT1).	[19]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Beta-1,3-galactosyl-O-glycosyl-glycoprotein beta-1,6-N-acetylglucosaminyltransferase (GCNT1).	[20]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Beta-1,3-galactosyl-O-glycosyl-glycoprotein beta-1,6-N-acetylglucosaminyltransferase (GCNT1).	[21]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Beta-1,3-galactosyl-O-glycosyl-glycoprotein beta-1,6-N-acetylglucosaminyltransferase (GCNT1).	[22]
Melphalan	DMOLNHF	Approved	Melphalan decreases the expression of Beta-1,3-galactosyl-O-glycosyl-glycoprotein beta-1,6-N-acetylglucosaminyltransferase (GCNT1).	[23]
Sulindac	DM2QHZU	Approved	Sulindac increases the expression of Beta-1,3-galactosyl-O-glycosyl-glycoprotein beta-1,6-N-acetylglucosaminyltransferase (GCNT1).	[24]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Beta-1,3-galactosyl-O-glycosyl-glycoprotein beta-1,6-N-acetylglucosaminyltransferase (GCNT1).	[25]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Beta-1,3-galactosyl-O-glycosyl-glycoprotein beta-1,6-N-acetylglucosaminyltransferase (GCNT1).	[26]
Seocalcitol	DMKL9QO	Phase 3	Seocalcitol decreases the expression of Beta-1,3-galactosyl-O-glycosyl-glycoprotein beta-1,6-N-acetylglucosaminyltransferase (GCNT1).	[27]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Beta-1,3-galactosyl-O-glycosyl-glycoprotein beta-1,6-N-acetylglucosaminyltransferase (GCNT1).	[28]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Beta-1,3-galactosyl-O-glycosyl-glycoprotein beta-1,6-N-acetylglucosaminyltransferase (GCNT1).	[29]

References

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• [2] Molecular Pathways: Mucins and Drug Delivery in Cancer.Clin Cancer Res. 2017 Mar 15;23(6):1373-1378. doi: 10.1158/1078-0432.CCR-16-0862. Epub 2016 Dec 30.
• [3] Clinicopathological significance of core 2 beta1,6-N-acetylglucosaminyltransferase messenger RNA expressed in the pulmonary adenocarcinoma determined by in situ hybridization.Cancer Res. 2001 Mar 1;61(5):2226-31.
• [4] Pancreas carcinoma antigen fused to invariant chain elicits T-cell response and tumor growth inhibition.Pancreas. 2008 Oct;37(3):321-7. doi: 10.1097/MPA.0b013e318166722e7.
• [5] Core 2 N-acetylglucosaminyltransferase-1 expression induces aggressive potential of testicular germ cell tumor.Int J Cancer. 2010 Sep 1;127(5):1052-9. doi: 10.1002/ijc.25117.
• [6] C2-O-sLeX glycoproteins are E-selectin ligands that regulate invasion of human colon and hepatic carcinoma cells.PLoS One. 2011 Jan 19;6(1):e16281. doi: 10.1371/journal.pone.0016281.
• [7] The high affinity selectin glycan ligand C2-O-sLex and mRNA transcripts of the core 2 beta-1,6-N-acetylglucosaminyltransferase (C2GnT1) gene are highly expressed in human colorectal adenocarcinomas.BMC Cancer. 2009 Mar 6;9:79. doi: 10.1186/1471-2407-9-79.
• [8] Carcinoma-associated expression of core 2 beta-1,6-N-acetylglucosaminyltransferase gene in human colorectal cancer: role of O-glycans in tumor progression.Cancer Res. 1997 Dec 1;57(23):5201-6.
• [9] Selective depletion of mouse kidney proximal straight tubule cells causes acute kidney injury.Transgenic Res. 2012 Feb;21(1):51-62. doi: 10.1007/s11248-011-9504-z. Epub 2011 Mar 24.
• [10] Aberrant O-glycosylation modulates aggressiveness in neuroblastoma.Oncotarget. 2018 Sep 25;9(75):34176-34188. doi: 10.18632/oncotarget.26169. eCollection 2018 Sep 25.
• [11] An A/G polymorphism of core 2 branching enzyme gene is associated with prostate cancer.Biochem Biophys Res Commun. 2005 Jun 17;331(4):958-63. doi: 10.1016/j.bbrc.2005.04.022.
• [12] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [13] Analysis of the in vitro synergistic effect of 5-fluorouracil and cisplatin on cervical carcinoma cells. Int J Gynecol Cancer. 2006 May-Jun;16(3):1321-9.
• [14] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [15] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [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] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [18] 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.
• [19] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [20] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [21] Unique transcriptome, pathways, and networks in the human endometrial fibroblast response to progesterone in endometriosis. Biol Reprod. 2011 Apr;84(4):801-15.
• [22] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [23] Bone marrow osteoblast damage by chemotherapeutic agents. PLoS One. 2012;7(2):e30758. doi: 10.1371/journal.pone.0030758. Epub 2012 Feb 17.
• [24] Growth-suppressive effect of non-steroidal anti-inflammatory drugs on 11 colon-cancer cell lines and fluorescence differential display of genes whose expression is influenced by sulindac. Int J Cancer. 2000 Dec 15;88(6):873-80. doi: 10.1002/1097-0215(20001215)88:6<873::aid-ijc6>3.0.co;2-b.
• [25] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [26] 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.
• [27] Expression profiling in squamous carcinoma cells reveals pleiotropic effects of vitamin D3 analog EB1089 signaling on cell proliferation, differentiation, and immune system regulation. Mol Endocrinol. 2002 Jun;16(6):1243-56.
• [28] Characterization of the Molecular Alterations Induced by the Prolonged Exposure of Normal Colon Mucosa and Colon Cancer Cells to Low-Dose Bisphenol A. Int J Mol Sci. 2022 Oct 1;23(19):11620. doi: 10.3390/ijms231911620.
• [29] 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.