Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTWFA0GJ)

• DOT Name: Heparan sulfate glucosamine 3-O-sulfotransferase 2 (HS3ST2)
• Synonyms: EC 2.8.2.29; Heparan sulfate D-glucosaminyl 3-O-sulfotransferase 2; 3-OST-2; Heparan sulfate 3-O-sulfotransferase 2; h3-OST-2
• Gene Name: HS3ST2
• Related Disease:
  Acute myelogenous leukaemia
  Adult lymphoma
  Breast cancer
  Breast carcinoma
  Cervical cancer
  Cervical carcinoma
  Endometrial cancer
  Endometrial carcinoma
  Epithelial ovarian cancer
  Lung cancer
  Lung carcinoma
  Lymphoma
  Neoplasm
  Non-small-cell lung cancer
  Pediatric lymphoma
  Squamous cell carcinoma
  Advanced cancer
  Colorectal carcinoma
• UniProt ID: HS3S2_HUMAN
• EC Number: 2.8.2.29
• Pfam ID: PF00685
• Sequence:
  MAYRVLGRAGPPQPRRARRLLFAFTLSLSCTYLCYSFLCCCDDLGRSRLLGAPRCLRGPS
  AGGQKLLQKSRPCDPSGPTPSEPSAPSAPAAAVPAPRLSGSNHSGSPKLGTKRLPQALIV
  GVKKGGTRAVLEFIRVHPDVRALGTEPHFFDRNYGRGLDWYRSLMPRTLESQITLEKTPS
  YFVTQEAPRRIFNMSRDTKLIVVVRNPVTRAISDYTQTLSKKPDIPTFEGLSFRNRTLGL
  VDVSWNAIRIGMYVLHLESWLQYFPLAQIHFVSGERLITDPAGEMGRVQDFLGIKRFITD
  KHFYFNKTKGFPCLKKTESSLLPRCLGKSKGRTHVQIDPEVIDQLREFYRPYNIKFYETV
  GQDFRWE
• Function: Sulfotransferase that utilizes 3'-phospho-5'-adenylyl sulfate (PAPS) to catalyze the transfer of a sulfo group to an N-unsubstituted glucosamine linked to a 2-O-sulfo iduronic acid unit on heparan sulfate. Catalyzes the O-sulfation of glucosamine in GlcA2S-GlcNS. Unlike HS3ST1/3-OST-1, does not convert non-anticoagulant heparan sulfate to anticoagulant heparan sulfate.
• Tissue Specificity: Highly expressed in the brain and weakly expressed in the heart, placenta, lung and skeletal muscle.
• KEGG Pathway: Glycosaminoglycan biosynthesis - heparan sulfate / heparin (hsa00534)
• Reactome Pathway: HS-GAG biosynthesis (R-HSA-2022928)
• BioCyc Pathway: MetaCyc:HS04557-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

18 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Definitive	Biomarker	[1]
Adult lymphoma	DISK8IZR	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[3]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[3]
Cervical cancer	DISFSHPF	Strong	Biomarker	[4]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[4]
Endometrial cancer	DISW0LMR	Strong	Biomarker	[5]
Endometrial carcinoma	DISXR5CY	Strong	Biomarker	[5]
Epithelial ovarian cancer	DIS56MH2	Strong	Posttranslational Modification	[6]
Lung cancer	DISCM4YA	Strong	Altered Expression	[7]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[7]
Lymphoma	DISN6V4S	Strong	Biomarker	[2]
Neoplasm	DISZKGEW	Strong	Biomarker	[8]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[7]
Pediatric lymphoma	DIS51BK2	Strong	Biomarker	[2]
Squamous cell carcinoma	DISQVIFL	Strong	Biomarker	[9]
Advanced cancer	DISAT1Z9	Disputed	Biomarker	[10]
Colorectal carcinoma	DIS5PYL0	Limited	Biomarker	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Heparan sulfate glucosamine 3-O-sulfotransferase 2 (HS3ST2).	[12]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Heparan sulfate glucosamine 3-O-sulfotransferase 2 (HS3ST2).	[13]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Heparan sulfate glucosamine 3-O-sulfotransferase 2 (HS3ST2).	[14]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate increases the expression of Heparan sulfate glucosamine 3-O-sulfotransferase 2 (HS3ST2).	[16]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Heparan sulfate glucosamine 3-O-sulfotransferase 2 (HS3ST2).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Folic acid	DMEMBJC	Approved	Folic acid increases the methylation of Heparan sulfate glucosamine 3-O-sulfotransferase 2 (HS3ST2).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Heparan sulfate glucosamine 3-O-sulfotransferase 2 (HS3ST2).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Heparan sulfate glucosamine 3-O-sulfotransferase 2 (HS3ST2).	[17]

References

• [1] DNA methylation analysis of ALOX12 and GSTM1 in acute myeloid leukaemia identifies prognostically significant groups.Br J Haematol. 2012 Oct;159(2):182-90. doi: 10.1111/bjh.12029. Epub 2012 Aug 28.
• [2] Pipeline for large-scale microdroplet bisulfite PCR-based sequencing allows the tracking of hepitype evolution in tumors.PLoS One. 2011;6(7):e21332. doi: 10.1371/journal.pone.0021332. Epub 2011 Jul 5.
• [3] The Pro-Tumoral Activity of Heparan Sulfate 3-O-Sulfotransferase 3B (HS3ST3B) in Breast Cancer MDA-MB-231 Cells Is Dependent on the Expression of Neuropilin-1.Molecules. 2018 Oct 22;23(10):2718. doi: 10.3390/molecules23102718.
• [4] Methylation in the promoters of HS3ST2 and CCNA1 genes is associated with cervical cancer in Uygur women in Xinjiang.Int J Biol Markers. 2014 Dec 9;29(4):e354-62. doi: 10.5301/jbm.5000107.
• [5] Methylation status of KLF4 and HS3ST2 genes as predictors of endometrial cancer and hyperplastic endometrial lesions.Int J Mol Med. 2018 Dec;42(6):3318-3328. doi: 10.3892/ijmm.2018.3872. Epub 2018 Sep 12.
• [6] Epigenetic loss of heparan sulfate 3-O-sulfation sensitizes ovarian carcinoma to oncogenic signals and predicts prognosis.Int J Cancer. 2018 Oct 15;143(8):1943-1953. doi: 10.1002/ijc.31580. Epub 2018 Aug 9.
• [7] Epigenetic inactivation of heparan sulfate (glucosamine) 3-O-sulfotransferase 2 in lung cancer and its role in tumorigenesis.PLoS One. 2013 Nov 12;8(11):e79634. doi: 10.1371/journal.pone.0079634. eCollection 2013.
• [8] Novel methylation panel for the early detection of neoplasia in high-risk ulcerative colitis and Crohn's colitis patients.Inflamm Bowel Dis. 2013 Jan;19(1):165-73. doi: 10.1002/ibd.22994.
• [9] Cervical dysplasia: assessing methylation status (Methylight) of CCNA1, DAPK1, HS3ST2, PAX1 and TFPI2 to improve diagnostic accuracy.Gynecol Oncol. 2010 Nov;119(2):225-31. doi: 10.1016/j.ygyno.2010.07.028. Epub 2010 Aug 13.
• [10] The heparan sulfate 3-O-sulfotransferases (HS3ST) 2, 3B and 4 enhance proliferation and survival in breast cancer MDA-MB-231 cells.PLoS One. 2018 Mar 16;13(3):e0194676. doi: 10.1371/journal.pone.0194676. eCollection 2018.
• [11] Aberrant methylation of heparan sulfate glucosamine 3-O-sulfotransferase 2 genes as a biomarker in colorectal cancer.Anticancer Res. 2010 Dec;30(12):4811-8.
• [12] 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.
• [13] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [14] 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.
• [15] Folic acid modulates cancer-associated micro RNAs and inflammatory mediators in neoplastic and non-neoplastic colonic cells in a different way. Mol Nutr Food Res. 2017 Dec;61(12). doi: 10.1002/mnfr.201700260. Epub 2017 Nov 9.
• [16] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [17] 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.