Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJJCVG1)

• DOT Name: Alpha-(1,6)-fucosyltransferase (FUT8)
• Synonyms: Alpha1-6FucT; EC 2.4.1.68; Fucosyltransferase 8; GDP-L-Fuc:N-acetyl-beta-D-glucosaminide alpha1,6-fucosyltransferase; GDP-fucose--glycoprotein fucosyltransferase; Glycoprotein 6-alpha-L-fucosyltransferase
• Gene Name: FUT8
• Related Disease:
  Breast cancer
  Breast carcinoma
  Acute erythroid leukemia
  Adenoma
  Advanced cancer
  Arteriosclerosis
  Atherosclerosis
  Brain disease
  Castration-resistant prostate carcinoma
  Colorectal carcinoma
  Congenital disorder of glycosylation
  Congenital disorder of glycosylation with defective fucosylation
  Congenital disorder of glycosylation with defective fucosylation 1
  Congenital glaucoma
  Diabetic kidney disease
  Epithelial ovarian cancer
  Glaucoma/ocular hypertension
  Hepatitis
  Hepatitis A virus infection
  Hepatitis C virus infection
  Hepatocellular carcinoma
  Intellectual disability
  Juvenile open angle glaucoma
  Lung carcinoma
  Neoplasm
  Oral cancer
  Prostate cancer
  Prostate carcinoma
  Pulmonary emphysema
  Pulmonary fibrosis
  Renal fibrosis
  Schizophrenia
  Chronic obstructive pulmonary disease
  Lung cancer
  Non-small-cell lung cancer
  Melanoma
  Metastatic malignant neoplasm
  Metastatic melanoma
  Nervous system inflammation
  Pancreatic ductal carcinoma
• UniProt ID: FUT8_HUMAN
• PDB ID: 2DE0; 6VLD; 6VLE; 6X5H; 6X5R; 6X5S; 6X5T; 6X5U
• EC Number: 2.4.1.68
• Pfam ID: PF19745 ; PF14604
• Sequence:
  MRPWTGSWRWIMLILFAWGTLLFYIGGHLVRDNDHPDHSSRELSKILAKLERLKQQNEDL
  RRMAESLRIPEGPIDQGPAIGRVRVLEEQLVKAKEQIENYKKQTRNGLGKDHEILRRRIE
  NGAKELWFFLQSELKKLKNLEGNELQRHADEFLLDLGHHERSIMTDLYYLSQTDGAGDWR
  EKEAKDLTELVQRRITYLQNPKDCSKAKKLVCNINKGCGYGCQLHHVVYCFMIAYGTQRT
  LILESQNWRYATGGWETVFRPVSETCTDRSGISTGHWSGEVKDKNVQVVELPIVDSLHPR
  PPYLPLAVPEDLADRLVRVHGDPAVWWVSQFVKYLIRPQPWLEKEIEEATKKLGFKHPVI
  GVHVRRTDKVGTEAAFHPIEEYMVHVEEHFQLLARRMQVDKKRVYLATDDPSLLKEAKTK
  YPNYEFISDNSISWSAGLHNRYTENSLRGVILDIHFLSQADFLVCTFSSQVCRVAYEIMQ
  TLHPDASANFHSLDDIYYFGGQNAHNQIAIYAHQPRTADEIPMEPGDIIGVAGNHWDGYS
  KGVNRKLGRTGLYPSYKVREKIETVKYPTYPEAEK
• Function: Catalyzes the addition of fucose in alpha 1-6 linkage to the first GlcNAc residue, next to the peptide chains in N-glycans.
• KEGG Pathway:
  N-Glycan biosynthesis (hsa00510)
  Various types of N-glycan biosynthesis (hsa00513)
  Glycosaminoglycan biosynthesis - keratan sulfate (hsa00533)
  Metabolic pathways (hsa01100)
  Transcriptio.l misregulation in cancer (hsa05202)
• Reactome Pathway:
  Reactions specific to the complex N-glycan synthesis pathway (R-HSA-975578)
  Maturation of spike protein (R-HSA-9694548)
• BioCyc Pathway: MetaCyc:HS00491-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

40 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Definitive	Biomarker	[1]
Breast carcinoma	DIS2UE88	Definitive	Biomarker	[1]
Acute erythroid leukemia	DISZFC1O	Strong	Altered Expression	[2]
Adenoma	DIS78ZEV	Strong	Altered Expression	[3]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[4]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[4]
Brain disease	DIS6ZC3X	Strong	Biomarker	[5]
Castration-resistant prostate carcinoma	DISVGAE6	Strong	Altered Expression	[6]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[7]
Congenital disorder of glycosylation	DIS400QP	Strong	Biomarker	[8]
Congenital disorder of glycosylation with defective fucosylation	DIS5PFT2	Strong	Genetic Variation	[9]
Congenital disorder of glycosylation with defective fucosylation 1	DIS3HJ60	Strong	Autosomal recessive	[10]
Congenital glaucoma	DISHN3GO	Strong	Genetic Variation	[8]
Diabetic kidney disease	DISJMWEY	Strong	Biomarker	[11]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[12]
Glaucoma/ocular hypertension	DISLBXBY	Strong	Biomarker	[8]
Hepatitis	DISXXX35	Strong	Altered Expression	[13]
Hepatitis A virus infection	DISUMFQV	Strong	Altered Expression	[13]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[14]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[15]
Intellectual disability	DISMBNXP	Strong	Biomarker	[16]
Juvenile open angle glaucoma	DISZ43T5	Strong	Genetic Variation	[8]
Lung carcinoma	DISTR26C	Strong	Biomarker	[17]
Neoplasm	DISZKGEW	Strong	Altered Expression	[7]
Oral cancer	DISLD42D	Strong	Altered Expression	[18]
Prostate cancer	DISF190Y	Strong	Altered Expression	[6]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[6]
Pulmonary emphysema	DIS5M7HZ	Strong	Altered Expression	[19]
Pulmonary fibrosis	DISQKVLA	Strong	Biomarker	[20]
Renal fibrosis	DISMHI3I	Strong	Altered Expression	[21]
Schizophrenia	DISSRV2N	Strong	Altered Expression	[22]
Chronic obstructive pulmonary disease	DISQCIRF	moderate	Altered Expression	[19]
Lung cancer	DISCM4YA	moderate	Biomarker	[17]
Non-small-cell lung cancer	DIS5Y6R9	moderate	Altered Expression	[23]
Melanoma	DIS1RRCY	Limited	Biomarker	[24]
Metastatic malignant neoplasm	DIS86UK6	Limited	Biomarker	[23]
Metastatic melanoma	DISSL43L	Limited	Altered Expression	[24]
Nervous system inflammation	DISB3X5A	Limited	Biomarker	[25]
Pancreatic ductal carcinoma	DIS26F9Q	Limited	Altered Expression	[26]

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Temozolomide	DMKECZD	Approved	Alpha-(1,6)-fucosyltransferase (FUT8) affects the response to substance of Temozolomide.	[46]
Etoposide	DMNH3PG	Approved	Alpha-(1,6)-fucosyltransferase (FUT8) affects the response to substance of Etoposide.	[47]
DTI-015	DMXZRW0	Approved	Alpha-(1,6)-fucosyltransferase (FUT8) affects the response to substance of DTI-015.	[46]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Alpha-(1,6)-fucosyltransferase (FUT8).	[27]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Alpha-(1,6)-fucosyltransferase (FUT8).	[28]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Alpha-(1,6)-fucosyltransferase (FUT8).	[29]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Alpha-(1,6)-fucosyltransferase (FUT8).	[30]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Alpha-(1,6)-fucosyltransferase (FUT8).	[31]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Alpha-(1,6)-fucosyltransferase (FUT8).	[32]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Alpha-(1,6)-fucosyltransferase (FUT8).	[33]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Alpha-(1,6)-fucosyltransferase (FUT8).	[35]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Alpha-(1,6)-fucosyltransferase (FUT8).	[36]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Alpha-(1,6)-fucosyltransferase (FUT8).	[37]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Alpha-(1,6)-fucosyltransferase (FUT8).	[38]
Isotretinoin	DM4QTBN	Approved	Isotretinoin increases the expression of Alpha-(1,6)-fucosyltransferase (FUT8).	[40]
Pyridoxal Phosphate	DMO2K0J	Approved	Pyridoxal Phosphate decreases the activity of Alpha-(1,6)-fucosyltransferase (FUT8).	[41]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Alpha-(1,6)-fucosyltransferase (FUT8).	[42]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Alpha-(1,6)-fucosyltransferase (FUT8).	[44]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride increases the expression of Alpha-(1,6)-fucosyltransferase (FUT8).	[45]
Guanosine-5'-Triphosphate	DMV2OJX	Investigative	Guanosine-5'-Triphosphate decreases the activity of Alpha-(1,6)-fucosyltransferase (FUT8).	[41]
Iodoacetamide	DMM4XVL	Investigative	Iodoacetamide decreases the activity of Alpha-(1,6)-fucosyltransferase (FUT8).	[41]
Phenylglyoxal	DMHW93J	Investigative	Phenylglyoxal decreases the activity of Alpha-(1,6)-fucosyltransferase (FUT8).	[41]
Guanosine-5'-Diphosphate	DM0MUKQ	Investigative	Guanosine-5'-Diphosphate decreases the activity of Alpha-(1,6)-fucosyltransferase (FUT8).	[41]
Guanosine-5'-Monophosphate	DM3SLZK	Investigative	Guanosine-5'-Monophosphate decreases the activity of Alpha-(1,6)-fucosyltransferase (FUT8).	[41]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Alpha-(1,6)-fucosyltransferase (FUT8).	[34]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the methylation of Alpha-(1,6)-fucosyltransferase (FUT8).	[39]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Alpha-(1,6)-fucosyltransferase (FUT8).	[43]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Alpha-(1,6)-fucosyltransferase (FUT8).	[39]

References

• [1] Fucosyltransferase 8 deficiency suppresses breast cancer cell migration by interference of the FAK/integrin pathway.Cancer Biomark. 2019;25(4):303-311. doi: 10.3233/CBM-190209.
• [2] -1,6-Fucosyltransferase (FUT8) inhibits hemoglobin production during differentiation of murine and K562 human erythroleukemia cells.J Biol Chem. 2013 Jun 7;288(23):16839-16847. doi: 10.1074/jbc.M113.459594. Epub 2013 Apr 22.
• [3] Fucosylation is associated with the malignant transformation of intraductal papillary mucinous neoplasms: a lectin microarray-based study.Surg Today. 2016 Oct;46(10):1217-23. doi: 10.1007/s00595-015-1299-8. Epub 2016 Jan 11.
• [4] Lysophosphatidic acid decreased macrophage foam cell migration correlated with downregulation of fucosyltransferase 8 via HNF1.Atherosclerosis. 2019 Nov;290:19-30. doi: 10.1016/j.atherosclerosis.2019.09.001. Epub 2019 Sep 11.
• [5] Deficiency of 1,6-fucosyltransferase promotes neuroinflammation by increasing the sensitivity of glial cells to inflammatory mediators.Biochim Biophys Acta Gen Subj. 2019 Mar;1863(3):598-608. doi: 10.1016/j.bbagen.2018.12.008. Epub 2018 Dec 17.
• [6] Overexpression of (1,6) fucosyltransferase in the development of castration-resistant prostate cancer cells.Prostate Cancer Prostatic Dis. 2018 Apr;21(1):137-146. doi: 10.1038/s41391-017-0016-7. Epub 2018 Jan 16.
• [7] Prognostic role of FUT8 expression in relation to p53 status in stage II and III colorectal cancer.PLoS One. 2018 Jul 5;13(7):e0200315. doi: 10.1371/journal.pone.0200315. eCollection 2018.
• [8] Childhood glaucoma in association with congenital disorder of glycosylation caused by mutations in fucosyltransferase 8.J AAPOS. 2019 Dec;23(6):351-352. doi: 10.1016/j.jaapos.2019.08.272. Epub 2019 Sep 30.
• [9] Autozygome and high throughput confirmation of disease genes candidacy. Genet Med. 2019 Mar;21(3):736-742. doi: 10.1038/s41436-018-0138-x. Epub 2018 Sep 21.
• [10] Biallelic Mutations in FUT8 Cause a Congenital Disorder of Glycosylation with Defective Fucosylation. Am J Hum Genet. 2018 Jan 4;102(1):188-195. doi: 10.1016/j.ajhg.2017.12.009.
• [11] Inhibition of core fucosylation limits progression of diabetic kidney disease.Biochem Biophys Res Commun. 2019 Dec 10;520(3):612-618. doi: 10.1016/j.bbrc.2019.10.037. Epub 2019 Oct 14.
• [12] Core fucosylation of copper transporter 1 plays a crucial role in cisplatin-resistance of epithelial ovarian cancer by regulating drug uptake.Mol Carcinog. 2019 May;58(5):794-807. doi: 10.1002/mc.22971. Epub 2019 Jan 21.
• [13] The alpha1-6-fucosyltransferase gene and its biological significance.Biochim Biophys Acta. 1999 Dec 6;1473(1):9-20. doi: 10.1016/s0304-4165(99)00166-x.
• [14] Hepatitis C Virus-Induced FUT8 Causes 5-FU Drug Resistance in Human Hepatoma Huh7.5.1 Cells.Viruses. 2019 Apr 24;11(4):378. doi: 10.3390/v11040378.
• [15] Activated p53 with Histone Deacetylase Inhibitor Enhances L-Fucose-Mediated Drug Delivery through Induction of Fucosyltransferase 8 Expression in Hepatocellular Carcinoma Cells.PLoS One. 2016 Dec 15;11(12):e0168355. doi: 10.1371/journal.pone.0168355. eCollection 2016.
• [16] Core fucosylation of N-linked glycans in leukocyte adhesion deficiency/congenital disorder of glycosylation IIc fibroblasts.Glycobiology. 2005 Oct;15(10):924-34. doi: 10.1093/glycob/cwi081. Epub 2005 May 25.
• [17] An integromic signature for lung cancer early detection.Oncotarget. 2018 May 15;9(37):24684-24692. doi: 10.18632/oncotarget.25227. eCollection 2018 May 15.
• [18] Glycoproteomic identification of novel plasma biomarkers for oral cancer.J Food Drug Anal. 2019 Apr;27(2):483-493. doi: 10.1016/j.jfda.2018.12.008. Epub 2019 Jan 8.
• [19] 1,6-Fucosyltransferase (Fut8) is implicated in vulnerability to elastase-induced emphysema in mice and a possible non-invasive predictive marker for disease progression and exacerbations in chronic obstructive pulmonary disease (COPD).Biochem Biophys Res Commun. 2012 Jul 20;424(1):112-7. doi: 10.1016/j.bbrc.2012.06.081. Epub 2012 Jun 23.
• [20] The effect of core fucosylation-mediated regulation of multiple signaling pathways on lung pericyte activation and fibrosis.Int J Biochem Cell Biol. 2019 Dec;117:105639. doi: 10.1016/j.biocel.2019.105639. Epub 2019 Oct 24.
• [21] Inhibition of TGF-1-receptor posttranslational core fucosylation attenuates rat renal interstitial fibrosis.Kidney Int. 2013 Jul;84(1):64-77. doi: 10.1038/ki.2013.82. Epub 2013 Mar 13.
• [22] Altered fucosyltransferase expression in the superior temporal gyrus of elderly patients with schizophrenia.Schizophr Res. 2017 Apr;182:66-73. doi: 10.1016/j.schres.2016.10.024. Epub 2016 Oct 20.
• [23] MicroRNA-198-5p inhibits the migration and invasion of non-small lung cancer cells by targeting fucosyltransferase 8.Clin Exp Pharmacol Physiol. 2019 Oct;46(10):955-967. doi: 10.1111/1440-1681.13154. Epub 2019 Aug 30.
• [24] A Systems Biology Approach Identifies FUT8 as a Driver of Melanoma Metastasis.Cancer Cell. 2017 Jun 12;31(6):804-819.e7. doi: 10.1016/j.ccell.2017.05.007.
• [25] Core Fucosylation of the T Cell Receptor Is Required for T Cell Activation.Front Immunol. 2018 Jan 29;9:78. doi: 10.3389/fimmu.2018.00078. eCollection 2018.
• [26] Clinicopathological and prognostic significance of MUC13 and AGR2 expression in intraductal papillary mucinous neoplasms of the pancreas.Pancreatology. 2018 Jun;18(4):407-412. doi: 10.1016/j.pan.2018.04.003. Epub 2018 Apr 3.
• [27] 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.
• [28] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [29] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [30] 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.
• [31] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [32] The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
• [33] High-throughput ectopic expression screen for tamoxifen resistance identifies an atypical kinase that blocks autophagy. Proc Natl Acad Sci U S A. 2011 Feb 1;108(5):2058-63.
• [34] 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.
• [35] 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.
• [36] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [37] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [38] 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.
• [39] 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.
• [40] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [41] Chemical modifications of alpha1,6-fucosyltransferase define amino acid residues of catalytic importance. Biochimie. 2003 Mar-Apr;85(3-4):303-10. doi: 10.1016/s0300-9084(03)00074-9.
• [42] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [43] 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.
• [44] 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.
• [45] 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.
• [46] Tumor necrosis factor-alpha-induced protein 3 as a putative regulator of nuclear factor-kappaB-mediated resistance to O6-alkylating agents in human glioblastomas. J Clin Oncol. 2006 Jan 10;24(2):274-87. doi: 10.1200/JCO.2005.02.9405. Epub 2005 Dec 19.
• [47] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.