Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTPSUBN2)

• DOT Name: Beta-1,3-N-acetylglucosaminyltransferase lunatic fringe (LFNG)
• Synonyms: EC 2.4.1.222; O-fucosylpeptide 3-beta-N-acetylglucosaminyltransferase
• Gene Name: LFNG
• Related Disease:
  Spondylocostal dysostosis 3, autosomal recessive
  Breast neoplasm
  Dysplasia
  Pancreatic cancer
  Autosomal recessive spondylocostal dysostosis
  Osteochondrodysplasia
  Sickle-cell anaemia
  Skeletal dysplasia
  Spondylocostal dysostosis
  Systemic primary carnitine deficiency disease
• UniProt ID: LFNG_HUMAN
• EC Number: 2.4.1.222
• Pfam ID: PF02434
• Sequence:
  MLKRCGRRLLLALAGALLACLLVLTADPPPPPLPAERGRRALRSLAGPAGAAPAPGLGAA
  AAAPGALVRDVHSLSEYFSLLTRARRDAGPPPGAAPRPADGHPRPLAEPLAPRDVFIAVK
  TTKKFHRARLDLLLETWISRHKEMTFIFTDGEDEALARHTGNVVITNCSAAHSRQALSCK
  MAVEYDRFIESGRKWFCHVDDDNYVNLRALLRLLASYPHTRDVYVGKPSLDRPIQAMERV
  SENKVRPVHFWFATGGAGFCISRGLALKMSPWASGGHFMNTAERIRLPDDCTIGYIVEAL
  LGVPLIRSGLFHSHLENLQQVPTSELHEQVTLSYGMFENKRNAVHVKGPFSVEADPSRFR
  SIHCHLYPDTPWCPRTAIF
• Function: Glycosyltransferase that initiates the elongation of O-linked fucose residues attached to EGF-like repeats in the extracellular domain of Notch molecules. Modulates NOTCH1 activity by modifying O-fucose residues at specific EGF-like domains resulting in inhibition of NOTCH1 activation by JAG1 and enhancement of NOTCH1 activation by DLL1 via an increase in its binding to DLL1. Decreases the binding of JAG1 to NOTCH2 but not that of DLL1. Essential mediator of somite segmentation and patterning.
• KEGG Pathway:
  Other types of O-glycan biosynthesis (hsa00514)
  Notch sig.ling pathway (hsa04330)
  Human papillomavirus infection (hsa05165)
• Reactome Pathway:
  Defective LFNG causes SCDO3 (R-HSA-5083630)
  Somitogenesis (R-HSA-9824272)
  Pre-NOTCH Processing in Golgi (R-HSA-1912420)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Spondylocostal dysostosis 3, autosomal recessive	DIS10LTO	Definitive	Autosomal recessive	[1]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[2]
Dysplasia	DISHPNVX	Strong	Genetic Variation	[1]
Pancreatic cancer	DISJC981	Strong	Biomarker	[3]
Autosomal recessive spondylocostal dysostosis	DISAJI27	Supportive	Autosomal recessive	[4]
Osteochondrodysplasia	DIS9SPWW	Limited	Genetic Variation	[5]
Sickle-cell anaemia	DIS5YNZB	Limited	Genetic Variation	[5]
Skeletal dysplasia	DIS5Z8U6	Limited	Genetic Variation	[5]
Spondylocostal dysostosis	DISTPWFK	Limited	Genetic Variation	[6]
Systemic primary carnitine deficiency disease	DIS9OPZ4	Limited	Genetic Variation	[5]

1 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 Beta-1,3-N-acetylglucosaminyltransferase lunatic fringe (LFNG).	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Beta-1,3-N-acetylglucosaminyltransferase lunatic fringe (LFNG).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Beta-1,3-N-acetylglucosaminyltransferase lunatic fringe (LFNG).	[9]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Beta-1,3-N-acetylglucosaminyltransferase lunatic fringe (LFNG).	[10]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Beta-1,3-N-acetylglucosaminyltransferase lunatic fringe (LFNG).	[11]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Beta-1,3-N-acetylglucosaminyltransferase lunatic fringe (LFNG).	[12]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Beta-1,3-N-acetylglucosaminyltransferase lunatic fringe (LFNG).	[13]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Beta-1,3-N-acetylglucosaminyltransferase lunatic fringe (LFNG).	[14]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Beta-1,3-N-acetylglucosaminyltransferase lunatic fringe (LFNG).	[15]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Beta-1,3-N-acetylglucosaminyltransferase lunatic fringe (LFNG).	[16]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Beta-1,3-N-acetylglucosaminyltransferase lunatic fringe (LFNG).	[17]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Beta-1,3-N-acetylglucosaminyltransferase lunatic fringe (LFNG).	[18]
Sulindac	DM2QHZU	Approved	Sulindac increases the expression of Beta-1,3-N-acetylglucosaminyltransferase lunatic fringe (LFNG).	[19]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Beta-1,3-N-acetylglucosaminyltransferase lunatic fringe (LFNG).	[20]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Beta-1,3-N-acetylglucosaminyltransferase lunatic fringe (LFNG).	[21]
OTX-015	DMI8RG1	Phase 1/2	OTX-015 increases the expression of Beta-1,3-N-acetylglucosaminyltransferase lunatic fringe (LFNG).	[22]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Beta-1,3-N-acetylglucosaminyltransferase lunatic fringe (LFNG).	[23]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Beta-1,3-N-acetylglucosaminyltransferase lunatic fringe (LFNG).	[24]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Beta-1,3-N-acetylglucosaminyltransferase lunatic fringe (LFNG).	[25]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Beta-1,3-N-acetylglucosaminyltransferase lunatic fringe (LFNG).	[26]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Beta-1,3-N-acetylglucosaminyltransferase lunatic fringe (LFNG).	[27]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Beta-1,3-N-acetylglucosaminyltransferase lunatic fringe (LFNG).	[28]
Propanoic Acid	DM9TN2W	Investigative	Propanoic Acid increases the expression of Beta-1,3-N-acetylglucosaminyltransferase lunatic fringe (LFNG).	[29]

References

• [1] Mutation of the LUNATIC FRINGE gene in humans causes spondylocostal dysostosis with a severe vertebral phenotype. Am J Hum Genet. 2006 Jan;78(1):28-37. doi: 10.1086/498879. Epub 2005 Nov 16.
• [2] Lunatic fringe deficiency cooperates with the Met/Caveolin gene amplicon to induce basal-like breast cancer.Cancer Cell. 2012 May 15;21(5):626-641. doi: 10.1016/j.ccr.2012.03.041.
• [3] Quantitative secretomic analysis of pancreatic cancer cells in serum-containing conditioned medium.Sci Rep. 2016 Nov 21;6:37606. doi: 10.1038/srep37606.
• [4] Spondylocostal Dysostosis, Autosomal Recessive. 2009 Aug 25 [updated 2023 Aug 17]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [5] Screening of known disease genes in congenital scoliosis.Mol Genet Genomic Med. 2018 Nov;6(6):966-974. doi: 10.1002/mgg3.466. Epub 2018 Sep 9.
• [6] Identification of novel LFNG mutations in spondylocostal dysostosis.J Hum Genet. 2019 Mar;64(3):261-264. doi: 10.1038/s10038-018-0548-2. Epub 2018 Dec 10.
• [7] 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.
• [8] 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.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [11] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [12] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [13] 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.
• [14] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [15] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [16] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [17] 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.
• [18] Cannabidiol enhances cytotoxicity of anti-cancer drugs in human head and neck squamous cell carcinoma. Sci Rep. 2020 Nov 26;10(1):20622. doi: 10.1038/s41598-020-77674-y.
• [19] Expression profile analysis of colon cancer cells in response to sulindac or aspirin. Biochem Biophys Res Commun. 2002 Mar 29;292(2):498-512.
• [20] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [21] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [22] Comprehensive transcriptome profiling of BET inhibitor-treated HepG2 cells. PLoS One. 2022 Apr 29;17(4):e0266966. doi: 10.1371/journal.pone.0266966. eCollection 2022.
• [23] 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.
• [24] Loss of TRIM33 causes resistance to BET bromodomain inhibitors through MYC- and TGF-beta-dependent mechanisms. Proc Natl Acad Sci U S A. 2016 Aug 2;113(31):E4558-66.
• [25] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [26] 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.
• [27] 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.
• [28] 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.
• [29] Propionic acid induces mitochondrial dysfunction and affects gene expression for mitochondria biogenesis and neuronal differentiation in SH-SY5Y cell line. Neurotoxicology. 2019 Dec;75:116-122. doi: 10.1016/j.neuro.2019.09.009. Epub 2019 Sep 14.