Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9BSDDQ)

• DOT Name: Polypeptide N-acetylgalactosaminyltransferase 14 (GALNT14)
• Synonyms: EC 2.4.1.41; Polypeptide GalNAc transferase 14; GalNAc-T14; pp-GaNTase 14; Protein-UDP acetylgalactosaminyltransferase 14; UDP-GalNAc:polypeptide N-acetylgalactosaminyltransferase 14
• Gene Name: GALNT14
• Related Disease:
  Autism
  Acute otitis media
  Adult glioblastoma
  Advanced cancer
  Esophageal squamous cell carcinoma
  Glioblastoma multiforme
  Hepatocellular carcinoma
  Lung adenocarcinoma
  Melanoma
  Narcolepsy
  Neoplasm
  Non-immune hydrops fetalis
  Non-small-cell lung cancer
  Otitis media
  Ovarian cancer
  Ovarian neoplasm
  Pancreatic cancer
  Signet ring cell carcinoma
  Acute myelogenous leukaemia
  Colorectal carcinoma
  Cornelia de Lange syndrome
  Keratoconus
  Metastatic malignant neoplasm
  Breast cancer
  Breast carcinoma
  Carcinoma of liver and intrahepatic biliary tract
  Liver cancer
  Neuroblastoma
• UniProt ID: GLT14_HUMAN
• EC Number: 2.4.1.41
• Pfam ID: PF00535 ; PF00652
• Sequence:
  MRRLTRRLVLPVFGVLWITVLLFFWVTKRKLEVPTGPEVQTPKPSDADWDDLWDQFDERR
  YLNAKKWRVGDDPYKLYAFNQRESERISSNRAIPDTRHLRCTLLVYCTDLPPTSIIITFH
  NEARSTLLRTIRSVLNRTPTHLIREIILVDDFSNDPDDCKQLIKLPKVKCLRNNERQGLV
  RSRIRGADIAQGTTLTFLDSHCEVNRDWLQPLLHRVKEDYTRVVCPVIDIINLDTFTYIE
  SASELRGGFDWSLHFQWEQLSPEQKARRLDPTEPIRTPIIAGGLFVIDKAWFDYLGKYDM
  DMDIWGGENFEISFRVWMCGGSLEIVPCSRVGHVFRKKHPYVFPDGNANTYIKNTKRTAE
  VWMDEYKQYYYAARPFALERPFGNVESRLDLRKNLRCQSFKWYLENIYPELSIPKESSIQ
  KGNIRQRQKCLESQRQNNQETPNLKLSPCAKVKGEDAKSQVWAFTYTQQILQEELCLSVI
  TLFPGAPVVLVLCKNGDDRQQWTKTGSHIEHIASHLCLDTDMFGDGTENGKEIVVNPCES
  SLMSQHWDMVSS
• Function: Catalyzes the initial reaction in O-linked oligosaccharide biosynthesis, the transfer of an N-acetyl-D-galactosamine residue to a serine or threonine residue on the protein receptor. Displays activity toward mucin-derived peptide substrates such as Muc2, Muc5AC, Muc7, and Muc13 (-58). May be involved in O-glycosylation in kidney.
• Tissue Specificity: Detected in renal tubules (at protein level). Highly expressed in fetal and adult kidney. Widely expressed at low level. Weakly expressed in whole brain, cerebellum, thymus, lung, mammary gland, liver, stomach, small intestine, colon, pancreas, spleen, bladder, uterus, placenta, testis, ovary, skeletal muscle, leukocyte, B-cell, bone marrow, fetal brain, fetal thymus, fetal lung, fetal liver, fetal small intestine, fetal spleen, fetal skeletal and fetus. Detected in renal tubules (at protein level).
• KEGG Pathway:
  Mucin type O-glycan biosynthesis (hsa00512)
  Other types of O-glycan biosynthesis (hsa00514)
  Metabolic pathways (hsa01100)
• Reactome Pathway: O-linked glycosylation of mucins (R-HSA-913709)

Molecular Interaction Atlas (MIA) of This DOT

28 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autism	DISV4V1Z	Definitive	Genetic Variation	[1]
Acute otitis media	DISL8D8G	Strong	Biomarker	[2]
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[3]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[4]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Genetic Variation	[5]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[3]
Hepatocellular carcinoma	DIS0J828	Strong	Genetic Variation	[6]
Lung adenocarcinoma	DISD51WR	Strong	Altered Expression	[4]
Melanoma	DIS1RRCY	Strong	Altered Expression	[7]
Narcolepsy	DISLCNLI	Strong	Genetic Variation	[8]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[9]
Non-immune hydrops fetalis	DISPUY8C	Strong	Genetic Variation	[10]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[4]
Otitis media	DISGZDUO	Strong	Biomarker	[2]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[11]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[11]
Pancreatic cancer	DISJC981	Strong	Biomarker	[7]
Signet ring cell carcinoma	DISVCUCR	Strong	Genetic Variation	[12]
Acute myelogenous leukaemia	DISCSPTN	moderate	Genetic Variation	[13]
Colorectal carcinoma	DIS5PYL0	moderate	Genetic Variation	[12]
Cornelia de Lange syndrome	DISEQSXO	moderate	Genetic Variation	[14]
Keratoconus	DISOONXH	moderate	Biomarker	[15]
Metastatic malignant neoplasm	DIS86UK6	moderate	Biomarker	[16]
Breast cancer	DIS7DPX1	Limited	Biomarker	[17]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[17]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Limited	Genetic Variation	[18]
Liver cancer	DISDE4BI	Limited	Genetic Variation	[18]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[19]

9 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 Polypeptide N-acetylgalactosaminyltransferase 14 (GALNT14).	[20]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Polypeptide N-acetylgalactosaminyltransferase 14 (GALNT14).	[21]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Polypeptide N-acetylgalactosaminyltransferase 14 (GALNT14).	[22]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Polypeptide N-acetylgalactosaminyltransferase 14 (GALNT14).	[23]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Polypeptide N-acetylgalactosaminyltransferase 14 (GALNT14).	[24]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Polypeptide N-acetylgalactosaminyltransferase 14 (GALNT14).	[25]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Polypeptide N-acetylgalactosaminyltransferase 14 (GALNT14).	[20]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Polypeptide N-acetylgalactosaminyltransferase 14 (GALNT14).	[27]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Polypeptide N-acetylgalactosaminyltransferase 14 (GALNT14).	[29]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Polypeptide N-acetylgalactosaminyltransferase 14 (GALNT14).	[26]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Polypeptide N-acetylgalactosaminyltransferase 14 (GALNT14).	[28]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Polypeptide N-acetylgalactosaminyltransferase 14 (GALNT14).	[26]

References

• [1] Individual common variants exert weak effects on the risk for autism spectrum disorders.Hum Mol Genet. 2012 Nov 1;21(21):4781-92. doi: 10.1093/hmg/dds301. Epub 2012 Jul 26.
• [2] Genome-wide association study to identify the genetic determinants of otitis media susceptibility in childhood.PLoS One. 2012;7(10):e48215. doi: 10.1371/journal.pone.0048215. Epub 2012 Oct 25.
• [3] Effects of IGFBP-3 and GalNAc-T14 on proliferation and cell cycle of glioblastoma cells and its mechanism.J Pharm Pharmacol. 2020 Feb;72(2):218-226. doi: 10.1111/jphp.13187. Epub 2019 Nov 12.
• [4] GalNAc-T14 promotes metastasis through Wnt dependent HOXB9 expression in lung adenocarcinoma.Oncotarget. 2015 Dec 8;6(39):41916-28. doi: 10.18632/oncotarget.6019.
• [5] GALNT14 genotype as a response predictor for concurrent chemoradiotherapy in advanced esophageal squamous cell carcinoma.Oncotarget. 2017 Apr 25;8(17):29151-29160. doi: 10.18632/oncotarget.16253.
• [6] A GALNT14 rs9679162 genotype-guided therapeutic strategy for advanced hepatocellular carcinoma: systemic or hepatic arterial infusion chemotherapy.Pharmacogenomics J. 2020 Feb;20(1):57-68. doi: 10.1038/s41397-019-0106-0. Epub 2019 Oct 14.
• [7] Death-receptor O-glycosylation controls tumor-cell sensitivity to the proapoptotic ligand Apo2L/TRAIL.Nat Med. 2007 Sep;13(9):1070-7. doi: 10.1038/nm1627. Epub 2007 Sep 2.
• [8] Genome-wide association database developed in the Japanese Integrated Database Project.J Hum Genet. 2009 Sep;54(9):543-6. doi: 10.1038/jhg.2009.68. Epub 2009 Jul 24.
• [9] GALNT14 Genotype Predicts Postoperative Outcome of Stage III Colorectal Cancer With Oxaliplatin as Adjuvant Chemotherapy.Medicine (Baltimore). 2016 Apr;95(17):e3487. doi: 10.1097/MD.0000000000003487.
• [10] Identification of embryonic lethal genes in humans by autozygosity mapping and exome sequencing in consanguineous families. Genome Biol. 2015 Jun 3;16(1):116. doi: 10.1186/s13059-015-0681-6.
• [11] MiR-125a regulates ovarian cancer proliferation and invasion by repressing GALNT14 expression.Biomed Pharmacother. 2016 May;80:381-387. doi: 10.1016/j.biopha.2015.12.027. Epub 2016 Apr 8.
• [12] Prognostic Stratification of Advanced Gastric Signet Ring Cell Carcinoma by Clinicopathological Factors and GALNT14 Genotype.J Cancer. 2018 Sep 8;9(19):3540-3547. doi: 10.7150/jca.26293. eCollection 2018.
• [13] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [14] Rare copy number variants contribute pathogenic alleles in patients with intestinal malrotation.Mol Genet Genomic Med. 2019 Mar;7(3):e549. doi: 10.1002/mgg3.549. Epub 2019 Jan 10.
• [15] Autosomal Recessive Non-syndromic Keratoconus: Homozygous Frameshift Variant in the Candidate Novel Gene GALNT14.Curr Mol Med. 2019;19(9):683-687. doi: 10.2174/1566524019666190730095630.
• [16] GALNT14 promotes lung-specific breast cancer metastasis by modulating self-renewal and interaction with the lung microenvironment.Nat Commun. 2016 Dec 16;7:13796. doi: 10.1038/ncomms13796.
• [17] EFEMP2 Mediates GALNT14-Dependent Breast Cancer Cell Invasion.Transl Oncol. 2018 Apr;11(2):346-352. doi: 10.1016/j.tranon.2018.01.021. Epub 2018 Feb 8.
• [18] GALNT14 genotype effectively predicts the therapeutic response in unresectable hepatocellular carcinoma treated with transcatheter arterial chemoembolization.Pharmacogenomics. 2016 Mar;17(4):353-66. doi: 10.2217/pgs.15.179. Epub 2016 Feb 12.
• [19] Identification of GALNT14 as a novel neuroblastoma predisposition gene.Oncotarget. 2015 Sep 22;6(28):26335-46. doi: 10.18632/oncotarget.4501.
• [20] 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.
• [21] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [22] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [23] 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.
• [24] 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.
• [25] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [26] 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.
• [27] 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.
• [28] 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.
• [29] BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell. 2011 Sep 16;146(6):904-17.