Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTGND2YZ)

• DOT Name: Alpha-N-acetylneuraminide alpha-2,8-sialyltransferase (ST8SIA1)
• Synonyms: EC 2.4.3.8; Alpha-2,8-sialyltransferase 8A; Ganglioside GD3 synthase; Ganglioside GT3 synthase; Sialyltransferase 8A; SIAT8-A; Sialyltransferase St8Sia I; ST8SiaI
• Gene Name: ST8SIA1
• Related Disease:
  Melanoma
  Adult glioblastoma
  Advanced cancer
  Alzheimer disease
  Atherosclerosis
  Breast neoplasm
  Colorectal carcinoma
  Glioblastoma multiforme
  Glioma
  Immunodeficiency
  Lung cancer
  Lung neoplasm
  Neoplasm
  Neuroblastoma
  Parkinsonian disorder
  Triple negative breast cancer
  Breast carcinoma
  Breast cancer
  Invasive ductal breast carcinoma
• UniProt ID: SIA8A_HUMAN
• EC Number: 2.4.3.8
• Pfam ID: PF00777
• Sequence:
  MSPCGRARRQTSRGAMAVLAWKFPRTRLPMGASALCVVVLCWLYIFPVYRLPNEKEIVQG
  VLQQGTAWRRNQTAARAFRKQMEDCCDPAHLFAMTKMNSPMGKSMWYDGEFLYSFTIDNS
  TYSLFPQATPFQLPLKKCAVVGNGGILKKSGCGRQIDEANFVMRCNLPPLSSEYTKDVGS
  KSQLVTANPSIIRQRFQNLLWSRKTFVDNMKIYNHSYIYMPAFSMKTGTEPSLRVYYTLS
  DVGANQTVLFANPNFLRSIGKFWKSRGIHAKRLSTGLFLVSAALGLCEEVAIYGFWPFSV
  NMHEQPISHHYYDNVLPFSGFHAMPEEFLQLWYLHKIGALRMQLDPCEDTSLQPTS
• Function: Catalyzes the addition of sialic acid in alpha 2,8-linkage to the sialic acid moiety of the ganglioside GM3 to form ganglioside GD3; gangliosides are a subfamily of complex glycosphingolipds that contain one or more residues of sialic acid. Can catalyze the addition of a second alpha-2,8-sialic acid to GD3 to form GT3. Can use GM1b, GD1a and GT1b as acceptor substrates to synthesize GD1c, GT1a and GQ1b respectively. Can synthesize unusual tetra- and pentasialylated lactosylceramide derivatives identified as GQ3 (II3Neu5Ac4-Gg2Cer) and GP3 (II3Neu5Ac5-Gg2Cer) in breast cancer cells.
• Tissue Specificity: Strongly expressed in melanoma cell lines, adult and fetal brain and to a lesser extent in adult and fetal lung.
• KEGG Pathway:
  Glycosphingolipid biosynthesis - lacto and neolacto series (hsa00601)
  Glycosphingolipid biosynthesis - globo and isoglobo series (hsa00603)
  Glycosphingolipid biosynthesis - ganglio series (hsa00604)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Sialic acid metabolism (R-HSA-4085001)
• BioCyc Pathway: MetaCyc:HS03456-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

19 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Melanoma	DIS1RRCY	Definitive	Biomarker	[1]
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[2]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[2]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[3]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[4]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[5]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[6]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[2]
Glioma	DIS5RPEH	Strong	Biomarker	[7]
Immunodeficiency	DIS093I0	Strong	Biomarker	[8]
Lung cancer	DISCM4YA	Strong	Biomarker	[9]
Lung neoplasm	DISVARNB	Strong	Altered Expression	[9]
Neoplasm	DISZKGEW	Strong	Altered Expression	[10]
Neuroblastoma	DISVZBI4	Strong	Altered Expression	[2]
Parkinsonian disorder	DISHGY45	Strong	Biomarker	[11]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[12]
Breast carcinoma	DIS2UE88	moderate	Altered Expression	[10]
Breast cancer	DIS7DPX1	Limited	Altered Expression	[10]
Invasive ductal breast carcinoma	DIS43J58	Limited	Genetic Variation	[13]

8 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 Alpha-N-acetylneuraminide alpha-2,8-sialyltransferase (ST8SIA1).	[14]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Alpha-N-acetylneuraminide alpha-2,8-sialyltransferase (ST8SIA1).	[15]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Alpha-N-acetylneuraminide alpha-2,8-sialyltransferase (ST8SIA1).	[16]
DTI-015	DMXZRW0	Approved	DTI-015 increases the expression of Alpha-N-acetylneuraminide alpha-2,8-sialyltransferase (ST8SIA1).	[17]
GSK2110183	DMZHB37	Phase 2	GSK2110183 increases the expression of Alpha-N-acetylneuraminide alpha-2,8-sialyltransferase (ST8SIA1).	[18]
EMODIN	DMAEDQG	Terminated	EMODIN increases the expression of Alpha-N-acetylneuraminide alpha-2,8-sialyltransferase (ST8SIA1).	[20]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Alpha-N-acetylneuraminide alpha-2,8-sialyltransferase (ST8SIA1).	[21]
Cycloheximide	DMGDA3C	Investigative	Cycloheximide increases the expression of Alpha-N-acetylneuraminide alpha-2,8-sialyltransferase (ST8SIA1).	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Alpha-N-acetylneuraminide alpha-2,8-sialyltransferase (ST8SIA1).	[19]

References

• [1] TNF-signal and cAMP-mediated signals oppositely regulate melanoma- associated ganglioside GD3 synthase gene in human melanocytes.Sci Rep. 2019 Oct 14;9(1):14740. doi: 10.1038/s41598-019-51333-3.
• [2] Accumulation of unusual gangliosides G(Q3) and G(P3) in breast cancer cells expressing the G(D3) synthase.Molecules. 2012 Aug 10;17(8):9559-72. doi: 10.3390/molecules17089559.
• [3] Brain gangliosides of a transgenic mouse model of Alzheimer's disease with deficiency in GD3-synthase: expression of elevated levels of a cholinergic-specific ganglioside, GT1a.ASN Neuro. 2013 May 30;5(2):141-8. doi: 10.1042/AN20130006.
• [4] Disialoganglioside (GD3) synthase gene expression suppresses vascular smooth muscle cell responses via the inhibition of ERK1/2 phosphorylation, cell cycle progression, and matrix metalloproteinase-9 expression.J Biol Chem. 2004 Aug 6;279(32):33063-70. doi: 10.1074/jbc.M313462200. Epub 2004 Jun 2.
• [5] Interaction of glycosphingolipids GD3 and GD2 with growth factor receptors maintains breast cancer stem cell phenotype.Oncotarget. 2017 Jul 18;8(29):47454-47473. doi: 10.18632/oncotarget.17665.
• [6] MicroRNA-33a and let-7e inhibit human colorectal cancer progression by targeting ST8SIA1.Int J Biochem Cell Biol. 2017 Sep;90:48-58. doi: 10.1016/j.biocel.2017.07.016. Epub 2017 Jul 24.
• [7] Enhancement of malignant properties of human glioma cells by ganglioside GD3/GD2.Int J Oncol. 2018 Apr;52(4):1255-1266. doi: 10.3892/ijo.2018.4266. Epub 2018 Feb 7.
• [8] The ganglioside G(D2) induces the constitutive activation of c-Met in MDA-MB-231 breast cancer cells expressing the G(D3) synthase.Glycobiology. 2012 Jun;22(6):806-16. doi: 10.1093/glycob/cws049. Epub 2012 Feb 1.
• [9] Fundamental study of small interfering RNAs for ganglioside GD3 synthase gene as a therapeutic target of lung cancers.Oncogene. 2006 Nov 2;25(52):6924-35. doi: 10.1038/sj.onc.1209683. Epub 2006 Jul 24.
• [10] TNF differentially regulates ganglioside biosynthesis and expression in breast cancer cell lines.PLoS One. 2018 Apr 26;13(4):e0196369. doi: 10.1371/journal.pone.0196369. eCollection 2018.
• [11] Lentiviral-mediated knock-down of GD3 synthase protects against MPTP-induced motor deficits and neurodegeneration.Neurosci Lett. 2019 Jan 23;692:53-63. doi: 10.1016/j.neulet.2018.10.038. Epub 2018 Nov 1.
• [12] ST8SIA1 Regulates Tumor Growth and Metastasis in TNBC by Activating the FAK-AKT-mTOR Signaling Pathway.Mol Cancer Ther. 2018 Dec;17(12):2689-2701. doi: 10.1158/1535-7163.MCT-18-0399. Epub 2018 Sep 20.
• [13] GD?synthase expression enhances proliferation and tumor growth of MDA-MB-231 breast cancer cells through c-Met activation.Mol Cancer Res. 2010 Nov;8(11):1526-35. doi: 10.1158/1541-7786.MCR-10-0302. Epub 2010 Oct 1.
• [14] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [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] Unique transcriptome, pathways, and networks in the human endometrial fibroblast response to progesterone in endometriosis. Biol Reprod. 2011 Apr;84(4):801-15.
• [17] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [18] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [19] 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.
• [20] Gene expression alteration during redox-dependent enhancement of arsenic cytotoxicity by emodin in HeLa cells. Cell Res. 2005 Jul;15(7):511-22.
• [21] 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.
• [22] Comparative analysis of AhR-mediated TCDD-elicited gene expression in human liver adult stem cells. Toxicol Sci. 2009 Nov;112(1):229-44.