Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTRBBBD8)

• DOT Name: Alpha-2,8-sialyltransferase 8B (ST8SIA2)
• Synonyms: EC 2.4.3.-; Sialyltransferase 8B; SIAT8-B; Sialyltransferase St8Sia II; ST8SiaII; Sialyltransferase X; STX
• Gene Name: ST8SIA2
• Related Disease:
  Neuroblastoma
  Pervasive developmental disorder
  Adenocarcinoma
  Astrocytoma
  Autism
  Autism spectrum disorder
  Bacillary dysentery
  Bipolar disorder
  Bipolar I disorder
  Breast cancer
  Breast carcinoma
  Epilepsy
  Gastroenteritis
  Mental disorder
  Mood disorder
  Neoplasm
  Non-small-cell lung cancer
  Allergic rhinitis
  Rhabdomyosarcoma
  Advanced cancer
  Subarachnoid hemorrhage
  Schizophrenia
• UniProt ID: SIA8B_HUMAN
• EC Number: 2.4.3.-
• Pfam ID: PF00777
• Sequence:
  MQLQFRSWMLAALTLLVVFLIFADISEIEEEIGNSGGRGTIRSAVNSLHSKSNRAEVVIN
  GSSSPAVVDRSNESIKHNIQPASSKWRHNQTLSLRIRKQILKFLDAEKDISVLKGTLKPG
  DIIHYIFDRDSTMNVSQNLYELLPRTSPLKNKHFGTCAIVGNSGVLLNSGCGQEIDAHSF
  VIRCNLAPVQEYARDVGLKTDLVTMNPSVIQRAFEDLVNATWREKLLQRLHSLNGSILWI
  PAFMARGGKERVEWVNELILKHHVNVRTAYPSLRLLHAVRGYWLTNKVHIKRPTTGLLMY
  TLATRFCKQIYLYGFWPFPLDQNQNPVKYHYYDSLKYGYTSQASPHTMPLEFKALKSLHE
  QGALKLTVGQCDGAT
• Function: Catalyzes the transfer of a sialic acid from a CMP-linked sialic acid donor onto a terminal alpha-2,3-, alpha-2,6-, or alpha-2,8-linked sialic acid of an N-linked glycan acceptor through alpha-2,8-linkages (Probable). Therefore, participates in polysialic acid synthesis on various sialylated N-acetyllactosaminyl oligosaccharides (alpha-2,3-, alpha-2,6-, or alpha-2,8-linked sialic acid), including NCAM1, NCAM1 N-glycans, FETUB N-glycans, and to a lesser extent sialylparagloboside (SPG) and AHSG, which does not require the initial addition of an alpha 2,8-sialic acid (Probable). However, does not exhibit sialic acid-polymerase activity. Catalyzes polysialic acid synthesis in the hippocampal on NCAM1 and supports neurite outgrowth. ST8SIA2-mediated polysialylation influences on oligodendrocyte differentiation and may promote the integrity of myelin and axons.
• Tissue Specificity: Highly expressed in fetal brain, kidney and heart and to a much lesser extent in adult heart and thymus.
• Reactome Pathway:
  NCAM1 interactions (R-HSA-419037)
  N-Glycan antennae elongation (R-HSA-975577)
  Sialic acid metabolism (R-HSA-4085001)

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neuroblastoma	DISVZBI4	Definitive	Genetic Variation	[1]
Pervasive developmental disorder	DIS51975	Definitive	Genetic Variation	[1]
Adenocarcinoma	DIS3IHTY	Strong	Genetic Variation	[1]
Astrocytoma	DISL3V18	Strong	Altered Expression	[2]
Autism	DISV4V1Z	Strong	Biomarker	[3]
Autism spectrum disorder	DISXK8NV	Strong	Genetic Variation	[1]
Bacillary dysentery	DISFZHKN	Strong	Biomarker	[4]
Bipolar disorder	DISAM7J2	Strong	Genetic Variation	[5]
Bipolar I disorder	DISD09EH	Strong	Biomarker	[6]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[7]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[7]
Epilepsy	DISBB28L	Strong	Genetic Variation	[8]
Gastroenteritis	DISXQCG5	Strong	Biomarker	[9]
Mental disorder	DIS3J5R8	Strong	Biomarker	[3]
Mood disorder	DISLVMWO	Strong	Biomarker	[10]
Neoplasm	DISZKGEW	Strong	Biomarker	[11]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[12]
Allergic rhinitis	DIS3U9HN	moderate	Genetic Variation	[13]
Rhabdomyosarcoma	DISNR7MS	moderate	Biomarker	[14]
Advanced cancer	DISAT1Z9	Disputed	Biomarker	[12]
Subarachnoid hemorrhage	DISI7I8Y	Disputed	Biomarker	[15]
Schizophrenia	DISSRV2N	Limited	Autosomal dominant	[16]

3 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 Alpha-2,8-sialyltransferase 8B (ST8SIA2).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Alpha-2,8-sialyltransferase 8B (ST8SIA2).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Alpha-2,8-sialyltransferase 8B (ST8SIA2).	[26]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Alpha-2,8-sialyltransferase 8B (ST8SIA2).	[18]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Alpha-2,8-sialyltransferase 8B (ST8SIA2).	[19]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Alpha-2,8-sialyltransferase 8B (ST8SIA2).	[20]
Panobinostat	DM58WKG	Approved	Panobinostat affects the expression of Alpha-2,8-sialyltransferase 8B (ST8SIA2).	[21]
Azacitidine	DMTA5OE	Approved	Azacitidine decreases the expression of Alpha-2,8-sialyltransferase 8B (ST8SIA2).	[22]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Alpha-2,8-sialyltransferase 8B (ST8SIA2).	[23]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 affects the expression of Alpha-2,8-sialyltransferase 8B (ST8SIA2).	[21]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Alpha-2,8-sialyltransferase 8B (ST8SIA2).	[25]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Alpha-2,8-sialyltransferase 8B (ST8SIA2).	[27]

References

• [1] Effects of intronic single nucleotide polymorphisms (iSNPs) of a polysialyltransferase, ST8SIA2 gene found in psychiatric disorders on its gene products.Biochem Biophys Res Commun. 2016 Sep 23;478(3):1123-9. doi: 10.1016/j.bbrc.2016.08.079. Epub 2016 Aug 24.
• [2] Expression profiling of glycosyltransferases and related enzymes using in situ hybridization.Methods Enzymol. 2006;416:120-9. doi: 10.1016/S0076-6879(06)16008-5.
• [3] Cell-autonomous impact of polysialic acid-producing enzyme ST8SIA2 on developmental migration and distribution of cortical interneurons.J Neurochem. 2020 Feb;152(3):333-349. doi: 10.1111/jnc.14896. Epub 2019 Nov 26.
• [4] Evaluation of the GeneFields EHEC/SS PCR dipstick DNA chromatography kit for the detection of enteric bacterial pathogens in stool specimens of healthy humans.J Microbiol Methods. 2019 Jun;161:111-117. doi: 10.1016/j.mimet.2019.04.016. Epub 2019 May 2.
• [5] Chlorpromazine Increases the Expression of Polysialic Acid (PolySia) in Human Neuroblastoma Cells and Mouse Prefrontal Cortex.Int J Mol Sci. 2017 May 24;18(6):1123. doi: 10.3390/ijms18061123.
• [6] Association between ST8SIA2 and the Risk of Schizophrenia and Bipolar I Disorder across Diagnostic Boundaries.PLoS One. 2015 Sep 29;10(9):e0139413. doi: 10.1371/journal.pone.0139413. eCollection 2015.
• [7] Enhanced expression of polysialic acid correlates with malignant phenotype in breast cancer cell lines and clinical tissue samples.Int J Mol Med. 2016 Jan;37(1):197-206. doi: 10.3892/ijmm.2015.2395. Epub 2015 Oct 27.
• [8] Characterization of a 520 kb deletion on chromosome 15q26.1 including ST8SIA2 in a patient with behavioral disturbance, autism spectrum disorder, and epilepsy.Am J Med Genet A. 2014 Mar;164A(3):782-8. doi: 10.1002/ajmg.a.36345. Epub 2013 Dec 19.
• [9] Association of atypical enteropathogenic Escherichia coli (EPEC) with prolonged diarrhoea.J Med Microbiol. 2004 Nov;53(Pt 11):1137-1144. doi: 10.1099/jmm.0.45719-0.
• [10] Identification of sialyltransferase 8B as a generalized susceptibility gene for psychotic and mood disorders on chromosome 15q25-26.PLoS One. 2012;7(5):e38172. doi: 10.1371/journal.pone.0038172. Epub 2012 May 31.
• [11] The anti-tumor activity of the STAT3 inhibitor STX-0119 occurs via promotion of tumor-infiltrating lymphocyte accumulation in temozolomide-resistant glioblastoma cell line.Immunol Lett. 2017 Oct;190:20-25. doi: 10.1016/j.imlet.2017.07.005. Epub 2017 Jul 15.
• [12] Characterization of Distinct Populations of Carcinoma-Associated Fibroblasts from Non-Small Cell Lung Carcinoma Reveals a Role for ST8SIA2 in Cancer Cell Invasion.Neoplasia. 2019 May;21(5):482-493. doi: 10.1016/j.neo.2019.03.009. Epub 2019 Apr 9.
• [13] Integrated genome-wide association, coexpression network, and expression single nucleotide polymorphism analysis identifies novel pathway in allergic rhinitis.BMC Med Genomics. 2014 Aug 2;7:48. doi: 10.1186/1755-8794-7-48.
• [14] Intrabodies against the Polysialyltransferases ST8SiaII and ST8SiaIV inhibit Polysialylation of NCAM in rhabdomyosarcoma tumor cells.BMC Biotechnol. 2017 May 12;17(1):42. doi: 10.1186/s12896-017-0360-7.
• [15] Stereotactic Catheter Ventriculocisternostomy for Clearance of Subarachnoid Hemorrhage in Patients with Coiled Aneurysms.Oper Neurosurg (Hagerstown). 2018 Mar 1;14(3):231-235. doi: 10.1093/ons/opx129.
• [16] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [17] 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.
• [18] 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.
• [19] 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.
• [20] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [21] The Bromodomain Inhibitor JQ1 and the Histone Deacetylase Inhibitor Panobinostat Synergistically Reduce N-Myc Expression and Induce Anticancer Effects. Clin Cancer Res. 2016 May 15;22(10):2534-44. doi: 10.1158/1078-0432.CCR-15-1666. Epub 2016 Jan 5.
• [22] The effect of DNA methylation inhibitor 5-Aza-2'-deoxycytidine on human endometrial stromal cells. Hum Reprod. 2010 Nov;25(11):2859-69.
• [23] 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.
• [24] 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.
• [25] 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.
• [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] 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.