Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3JQD99)

• DOT Name: Alpha-N-acetylgalactosaminide alpha-2,6-sialyltransferase 1 (ST6GALNAC1)
• Synonyms: EC 2.4.3.3; GalNAc alpha-2,6-sialyltransferase I; ST6GalNAc I; ST6GalNAc-I; ST6GalNAcI; hST6GalNAc-I; Sialyltransferase 7A; SIAT7-A
• Gene Name: ST6GALNAC1
• Related Disease:
  Advanced cancer
  Bladder cancer
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Endometrial cancer
  Endometrial carcinoma
  Endometriosis
  Epithelial ovarian cancer
  Esophageal squamous cell carcinoma
  Gastric cancer
  Myocardial infarction
  Ovarian cancer
  Ovarian neoplasm
  Psychotic disorder
  Schizophrenia
  Stomach cancer
  Ulcerative colitis
  Urinary bladder cancer
  Urinary bladder neoplasm
• UniProt ID: SIA7A_HUMAN
• EC Number: 2.4.3.3
• Pfam ID: PF00777
• Sequence:
  MRSCLWRCRHLSQGVQWSLLLAVLVFFLFALPSFIKEPQTKPSRHQRTENIKERSLQSLA
  KPKSQAPTRARRTTIYAEPVPENNALNTQTQPKAHTTGDRGKEANQAPPEEQDKVPHTAQ
  RAAWKSPEKEKTMVNTLSPRGQDAGMASGRTEAQSWKSQDTKTTQGNGGQTRKLTASRTV
  SEKHQGKAATTAKTLIPKSQHRMLAPTGAVSTRTRQKGVTTAVIPPKEKKPQATPPPAPF
  QSPTTQRNQRLKAANFKSEPRWDFEEKYSFEIGGLQTTCPDSVKIKASKSLWLQKLFLPN
  LTLFLDSRHFNQSEWDRLEHFAPPFGFMELNYSLVQKVVTRFPPVPQQQLLLASLPAGSL
  RCITCAVVGNGGILNNSHMGQEIDSHDYVFRLSGALIKGYEQDVGTRTSFYGFTAFSLTQ
  SLLILGNRGFKNVPLGKDVRYLHFLEGTRDYEWLEALLMNQTVMSKNLFWFRHRPQEAFR
  EALHMDRYLLLHPDFLRYMKNRFLRSKTLDGAHWRIYRPTTGALLLLTALQLCDQVSAYG
  FITEGHERFSDHYYDTSWKRLIFYINHDFKLEREVWKRLHDEGIIRLYQRPGPGTAKAKN
• Function: Protein sialyltransferase specifically expressed in goblet cells that plays a key role in intestinal host-commensal homeostasis. Conjugates sialic acid with an alpha-2-6 linkage to N-acetylgalactosamine (GalNAc) glycan chains linked to serine or threonine in glycoproteins. Catalyzes the formation of the sialyl-Tn (S-Tn) antigen, an antigen found in intestinal goblet cells, as well as ulcerative colitis (UC) and various cancers. Protein sialylation in globlet cells is essential for mucus integrity and is required to protect the intestinal mucus against excessive bacterial proteolytic degradation.
• Tissue Specificity: Expression is restricted to the gastrointestinal tract . Highly expressed in goblet cells . Also expressed in various tumor cells .
• KEGG Pathway:
  Mucin type O-glycan biosynthesis (hsa00512)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Sialic acid metabolism (R-HSA-4085001)
• BioCyc Pathway: MetaCyc:HS00998-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

23 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Bladder cancer	DISUHNM0	Strong	Altered Expression	[2]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[3]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[3]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[4]
Colon cancer	DISVC52G	Strong	Altered Expression	[5]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[5]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[6]
Endometrial cancer	DISW0LMR	Strong	Genetic Variation	[7]
Endometrial carcinoma	DISXR5CY	Strong	Genetic Variation	[7]
Endometriosis	DISX1AG8	Strong	Altered Expression	[8]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[9]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[10]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[11]
Myocardial infarction	DIS655KI	Strong	Biomarker	[12]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[9]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[9]
Psychotic disorder	DIS4UQOT	Strong	Biomarker	[13]
Schizophrenia	DISSRV2N	Strong	Biomarker	[13]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[11]
Ulcerative colitis	DIS8K27O	Strong	Altered Expression	[5]
Urinary bladder cancer	DISDV4T7	Strong	Altered Expression	[2]
Urinary bladder neoplasm	DIS7HACE	Strong	Altered Expression	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Alpha-N-acetylgalactosaminide alpha-2,6-sialyltransferase 1 (ST6GALNAC1).	[14]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Alpha-N-acetylgalactosaminide alpha-2,6-sialyltransferase 1 (ST6GALNAC1).	[15]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Alpha-N-acetylgalactosaminide alpha-2,6-sialyltransferase 1 (ST6GALNAC1).	[15]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Alpha-N-acetylgalactosaminide alpha-2,6-sialyltransferase 1 (ST6GALNAC1).	[16]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Alpha-N-acetylgalactosaminide alpha-2,6-sialyltransferase 1 (ST6GALNAC1).	[17]
Enzalutamide	DMGL19D	Approved	Enzalutamide decreases the expression of Alpha-N-acetylgalactosaminide alpha-2,6-sialyltransferase 1 (ST6GALNAC1).	[18]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Alpha-N-acetylgalactosaminide alpha-2,6-sialyltransferase 1 (ST6GALNAC1).	[18]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Alpha-N-acetylgalactosaminide alpha-2,6-sialyltransferase 1 (ST6GALNAC1).	[20]

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-acetylgalactosaminide alpha-2,6-sialyltransferase 1 (ST6GALNAC1).	[19]

References

• [1] RNA splicing and splicing regulator changes in prostate cancer pathology.Hum Genet. 2017 Sep;136(9):1143-1154. doi: 10.1007/s00439-017-1792-9. Epub 2017 Apr 5.
• [2] Expression of sialyl-Tn sugar antigen in bladder cancer cells affects response to Bacillus Calmette Gurin (BCG) and to oxidative damage.Oncotarget. 2017 Apr 17;8(33):54506-54517. doi: 10.18632/oncotarget.17138. eCollection 2017 Aug 15.
• [3] Breast cancer cells expressing cancer-associated sialyl-Tn antigen have less capacity to develop osteolytic lesions in a mouse model of skeletal colonization.Clin Exp Metastasis. 2019 Dec;36(6):539-549. doi: 10.1007/s10585-019-09999-6. Epub 2019 Oct 8.
• [4] The ST6GalNAc-I sialyltransferase localizes throughout the Golgi and is responsible for the synthesis of the tumor-associated sialyl-Tn O-glycan in human breast cancer.J Biol Chem. 2006 Feb 10;281(6):3586-94. doi: 10.1074/jbc.M511826200. Epub 2005 Nov 30.
• [5] Cross-talk between Colon Cells and Macrophages Increases ST6GALNAC1 and MUC1-sTn Expression in Ulcerative Colitis and Colitis-Associated Colon Cancer.Cancer Immunol Res. 2020 Feb;8(2):167-178. doi: 10.1158/2326-6066.CIR-19-0514. Epub 2019 Dec 12.
• [6] ST6GALNAC1 plays important roles in enhancing cancer stem phenotypes of colorectal cancer via the Akt pathway.Oncotarget. 2017 Nov 8;8(68):112550-112564. doi: 10.18632/oncotarget.22545. eCollection 2017 Dec 22.
• [7] The Role of Sialyl-Tn in Cancer.Int J Mol Sci. 2016 Feb 24;17(3):275. doi: 10.3390/ijms17030275.
• [8] Reduced -2,6 sialylation regulates cell migration in endometriosis.Hum Reprod. 2019 Mar 1;34(3):479-490. doi: 10.1093/humrep/dey391.
• [9] Stimulative role of ST6GALNAC1 in proliferation, migration and invasion of ovarian cancer stem cells via the Akt signaling pathway.Cancer Cell Int. 2019 Apr 5;19:86. doi: 10.1186/s12935-019-0780-7. eCollection 2019.
• [10] Downregulation of ST6GALNAC1 is associated with esophageal squamous cell carcinoma development.Int J Oncol. 2017 Feb;50(2):441-447. doi: 10.3892/ijo.2016.3817. Epub 2016 Dec 22.
• [11] RNAi-mediated gene silencing of ST6GalNAc I suppresses the metastatic potential in gastric cancer cells.Gastric Cancer. 2016 Jan;19(1):85-97. doi: 10.1007/s10120-014-0454-z. Epub 2014 Dec 23.
• [12] Sialyltransferase7A, a Klf4-responsive gene, promotes cardiomyocyte apoptosis during myocardial infarction.Basic Res Cardiol. 2015 May;110(3):28. doi: 10.1007/s00395-015-0484-7. Epub 2015 Apr 10.
• [13] Disease-associated epigenetic changes in monozygotic twins discordant for schizophrenia and bipolar disorder.Hum Mol Genet. 2011 Dec 15;20(24):4786-96. doi: 10.1093/hmg/ddr416. Epub 2011 Sep 9.
• [14] Retinoic acid receptor alpha amplifications and retinoic acid sensitivity in breast cancers. Clin Breast Cancer. 2013 Oct;13(5):401-8.
• [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] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [18] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [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] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.