Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTB17Q43)

• DOT Name: Type 2 lactosamine alpha-2,3-sialyltransferase (ST3GAL6)
• Synonyms: EC 2.4.99.-; CMP-NeuAc:beta-galactoside alpha-2,3-sialyltransferase VI; ST3Gal VI; ST3GalVI; Sialyltransferase 10
• Gene Name: ST3GAL6
• Related Disease:
  Carcinoma
  Gastric neoplasm
  Hepatocellular carcinoma
  Neoplasm
  Plasma cell myeloma
  Triple negative breast cancer
  Colorectal carcinoma
• UniProt ID: SIA10_HUMAN
• EC Number: 2.4.99.-
• Pfam ID: PF00777
• Sequence:
  MRGYLVAIFLSAVFLYYVLHCILWGTNVYWVAPVEMKRRNKIQPCLSKPAFASLLRFHQF
  HPFLCAADFRKIASLYGSDKFDLPYGMRTSAEYFRLALSKLQSCDLFDEFDNIPCKKCVV
  VGNGGVLKNKTLGEKIDSYDVIIRMNNGPVLGHEEEVGRRTTFRLFYPESVFSDPIHNDP
  NTTVILTAFKPHDLRWLLELLMGDKINTNGFWKKPALNLIYKPYQIRILDPFIIRTAAYE
  LLHFPKVFPKNQKPKHPTTGIIAITLAFYICHEVHLAGFKYNFSDLKSPLHYYGNATMSL
  MNKNAYHNVTAEQLFLKDIIEKNLVINLTQD
• Function: Involved in the synthesis of sialyl-paragloboside, a precursor of sialyl-Lewis X determinant. Has a alpha-2,3-sialyltransferase activity toward Gal-beta1,4-GlcNAc structure on glycoproteins and glycolipids. Has a restricted substrate specificity, it utilizes Gal-beta1,4-GlcNAc on glycoproteins, and neolactotetraosylceramide and neolactohexaosylceramide, but not lactotetraosylceramide, lactosylceramide or asialo-GM1.
• Tissue Specificity: Ubiquitous.
• KEGG Pathway:
  Glycosphingolipid biosynthesis - lacto and neolacto series (hsa00601)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Keratan sulfate biosynthesis (R-HSA-2022854)
  Sialic acid metabolism (R-HSA-4085001)
  Lewis blood group biosynthesis (R-HSA-9037629)
  Pre-NOTCH Processing in Golgi (R-HSA-1912420)
• BioCyc Pathway: MetaCyc:ENSG00000064225-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Carcinoma	DISH9F1N	Strong	Posttranslational Modification	[1]
Gastric neoplasm	DISOKN4Y	Strong	Posttranslational Modification	[1]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[2]
Neoplasm	DISZKGEW	Strong	Biomarker	[3]
Plasma cell myeloma	DIS0DFZ0	Strong	Altered Expression	[3]
Triple negative breast cancer	DISAMG6N	Strong	Altered Expression	[4]
Colorectal carcinoma	DIS5PYL0	Limited	Biomarker	[5]

17 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 Type 2 lactosamine alpha-2,3-sialyltransferase (ST3GAL6).	[6]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Type 2 lactosamine alpha-2,3-sialyltransferase (ST3GAL6).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Type 2 lactosamine alpha-2,3-sialyltransferase (ST3GAL6).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Type 2 lactosamine alpha-2,3-sialyltransferase (ST3GAL6).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Type 2 lactosamine alpha-2,3-sialyltransferase (ST3GAL6).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Type 2 lactosamine alpha-2,3-sialyltransferase (ST3GAL6).	[11]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Type 2 lactosamine alpha-2,3-sialyltransferase (ST3GAL6).	[12]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Type 2 lactosamine alpha-2,3-sialyltransferase (ST3GAL6).	[13]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Type 2 lactosamine alpha-2,3-sialyltransferase (ST3GAL6).	[15]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Type 2 lactosamine alpha-2,3-sialyltransferase (ST3GAL6).	[16]
Azacitidine	DMTA5OE	Approved	Azacitidine increases the expression of Type 2 lactosamine alpha-2,3-sialyltransferase (ST3GAL6).	[17]
Cocaine	DMSOX7I	Approved	Cocaine increases the expression of Type 2 lactosamine alpha-2,3-sialyltransferase (ST3GAL6).	[18]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Type 2 lactosamine alpha-2,3-sialyltransferase (ST3GAL6).	[19]
PD-0325901	DM27D4J	Phase 2	PD-0325901 decreases the expression of Type 2 lactosamine alpha-2,3-sialyltransferase (ST3GAL6).	[20]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Type 2 lactosamine alpha-2,3-sialyltransferase (ST3GAL6).	[22]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Type 2 lactosamine alpha-2,3-sialyltransferase (ST3GAL6).	[23]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Type 2 lactosamine alpha-2,3-sialyltransferase (ST3GAL6).	[24]

2 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 Type 2 lactosamine alpha-2,3-sialyltransferase (ST3GAL6).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Type 2 lactosamine alpha-2,3-sialyltransferase (ST3GAL6).	[21]

References

• [1] DNA hypermethylation contributes to incomplete synthesis of carbohydrate determinants in gastrointestinal cancer.Gastroenterology. 2008 Jul;135(1):142-151.e3. doi: 10.1053/j.gastro.2008.03.031. Epub 2008 Mar 21.
• [2] Sialyltransferase ST3GAL6 mediates the effect of microRNA-26a on cell growth, migration, and invasion in hepatocellular carcinoma through the protein kinase B/mammalian target of rapamycin pathway.Cancer Sci. 2017 Feb;108(2):267-276. doi: 10.1111/cas.13128.
• [3] The sialyltransferase ST3GAL6 influences homing and survival in multiple myeloma.Blood. 2014 Sep 11;124(11):1765-76. doi: 10.1182/blood-2014-03-560862. Epub 2014 Jul 24.
• [4] Hypoxia and serum deprivation induces glycan alterations in triple negative breast cancer cells.Biol Chem. 2018 Jun 27;399(7):661-672. doi: 10.1515/hsz-2018-0121.
• [5] LncRNA ST3Gal6-AS1/ST3Gal6 axis mediates colorectal cancer progression by regulating -2,3 sialylation via PI3K/Akt signaling.Int J Cancer. 2019 Jul 15;145(2):450-460. doi: 10.1002/ijc.32103. Epub 2019 Jan 20.
• [6] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [7] 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.
• [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] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [10] 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.
• [11] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [12] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [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] 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.
• [15] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [16] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [17] The DNA methyltransferase inhibitors azacitidine, decitabine and zebularine exert differential effects on cancer gene expression in acute myeloid leukemia cells. Leukemia. 2009 Jun;23(6):1019-28.
• [18] Transcriptional profiling in the human prefrontal cortex: evidence for two activational states associated with cocaine abuse. Pharmacogenomics J. 2003;3(1):27-40.
• [19] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [20] PRC2 loss amplifies Ras-driven transcription and confers sensitivity to BRD4-based therapies. Nature. 2014 Oct 9;514(7521):247-51.
• [21] 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.
• [22] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [23] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [24] 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.