Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTESMIW5)

• DOT Name: Carbohydrate sulfotransferase 4 (CHST4)
• Synonyms: EC 2.8.2.-; Galactose/N-acetylglucosamine/N-acetylglucosamine 6-O-sulfotransferase 3; GST-3; High endothelial cells N-acetylglucosamine 6-O-sulfotransferase; HEC-GlcNAc6ST; L-selectin ligand sulfotransferase; LSST; N-acetylglucosamine 6-O-sulfotransferase 2; GlcNAc6ST-2; Gn6st-2
• Gene Name: CHST4
• Related Disease:
  Advanced cancer
  Colitis
  Colon cancer
  Colon carcinoma
  Colon mucinous adenocarcinoma
  Multiple endocrine neoplasia type 1
  Neoplasm
  Osteoarthritis
  Rheumatoid arthritis
  Adenoma
  Adenocarcinoma
  Mucinous adenocarcinoma
• UniProt ID: CHST4_HUMAN
• EC Number: 2.8.2.-
• Pfam ID: PF00685
• Sequence:
  MLLPKKMKLLLFLVSQMAILALFFHMYSHNISSLSMKAQPERMHVLVLSSWRSGSSFVGQ
  LFGQHPDVFYLMEPAWHVWMTFKQSTAWMLHMAVRDLIRAVFLCDMSVFDAYMEPGPRRQ
  SSLFQWENSRALCSAPACDIIPQDEIIPRAHCRLLCSQQPFEVVEKACRSYSHVVLKEVR
  FFNLQSLYPLLKDPSLNLHIVHLVRDPRAVFRSRERTKGDLMIDSRIVMGQHEQKLKKED
  QPYYVMQVICQSQLEIYKTIQSLPKALQERYLLVRYEDLARAPVAQTSRMYEFVGLEFLP
  HLQTWVHNITRGKGMGDHAFHTNARDALNVSQAWRWSLPYEKVSRLQKACGDAMNLLGYR
  HVRSEQEQRNLLLDLLSTWTVPEQIH
• Function: Sulfotransferase involved in SELL/L-selectin ligand biosynthesis pathway. Catalyzes the transfer of the sulfate group from 3'-phospho-5'-adenylyl sulfate (PAPS) onto the hydroxyl group at C-6 position of the non-reducing N-acetylglucosamine (GlcNAc) residue within O-linked mucin-type glycans. Contributes to generate sialyl 6-sulfo Lewis X determinant (also known as MECA-79 epitope) for SELL recognition, a prerequisite for continuous lymphocyte homing into peripheral lymph nodes and antigen immune surveillance. Transfers the sulfate group primarily on core 2 GlcNAcbeta1-6(Galbeta1-3)GalNAcalphaSer/Thr and extended core 1 GlcNAcbeta1-3Galbeta1-3GalNAcalphaSer/Thr based O-linked glycans on CD34 and GLYCAM1 peripheral node addressins (PNAds) expressed on the lumenal side of high endothelial venules (HEVs). The recognition of PNAds by SELL initiates a multistep process comprising tethering and rolling of blood lymphocytes on HEVs against the blood flow, followed by chemokine signaling, integrin-mediated lymphocyte adhesion onto endothelial cells and lymphocyte transendothelial migration. Modulates rolling velocity and differential T and B lymphocyte recruitment into peripheral lymph nodes, with a major role in B lymphocyte homing. Might be redundant in sulfation of MADCAM1 and lymphocyte trafficking to mesenteric lymph nodes. Can also sulfonate core 3 GlcNAcbeta1-3GalNAc-R based glycans as well as GlcNAcbeta1-3Galbeta1-Glc, GlcNAcbeta1-6ManOMe and GlcNAcbeta1-2Man oligosaccharides, which might be ectopically expressed during tumorigenesis.
• Tissue Specificity: Specifically expressed in HEV. Weakly expressed in spleen. Not expressed in other tissues. Expressed in colonic mucinous adenocarcinoma.
• KEGG Pathway: Glycosaminoglycan biosynthesis - keratan sulfate (hsa00533)
• Reactome Pathway: O-linked glycosylation of mucins (R-HSA-913709)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Colitis	DISAF7DD	Strong	Biomarker	[2]
Colon cancer	DISVC52G	Strong	Biomarker	[3]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[3]
Colon mucinous adenocarcinoma	DISXZXEI	Strong	Biomarker	[4]
Multiple endocrine neoplasia type 1	DIS0RJRK	Strong	Biomarker	[1]
Neoplasm	DISZKGEW	Strong	Biomarker	[1]
Osteoarthritis	DIS05URM	Strong	Altered Expression	[5]
Rheumatoid arthritis	DISTSB4J	Strong	Biomarker	[5]
Adenoma	DIS78ZEV	moderate	Altered Expression	[6]
Adenocarcinoma	DIS3IHTY	Limited	Altered Expression	[6]
Mucinous adenocarcinoma	DISKNFE8	Limited	Altered Expression	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Carbohydrate sulfotransferase 4 (CHST4).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Carbohydrate sulfotransferase 4 (CHST4).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Carbohydrate sulfotransferase 4 (CHST4).	[9]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Carbohydrate sulfotransferase 4 (CHST4).	[10]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Carbohydrate sulfotransferase 4 (CHST4).	[11]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Carbohydrate sulfotransferase 4 (CHST4).	[12]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Carbohydrate sulfotransferase 4 (CHST4).	[12]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Carbohydrate sulfotransferase 4 (CHST4).	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Carbohydrate sulfotransferase 4 (CHST4).	[15]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Carbohydrate sulfotransferase 4 (CHST4).	[16]

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 Carbohydrate sulfotransferase 4 (CHST4).	[13]

References

• [1] A radiation hybrid map of the proximal long arm of human chromosome 11 containing the multiple endocrine neoplasia type 1 (MEN-1) and bcl-1 disease loci.Am J Hum Genet. 1991 Dec;49(6):1189-96.
• [2] Role of MAdCAM-1-Expressing High Endothelial Venule-Like Vessels in Colitis Induced in Mice Lacking Sulfotransferases Catalyzing L-Selectin Ligand Biosynthesis.J Histochem Cytochem. 2018 Jun;66(6):415-425. doi: 10.1369/0022155417753363. Epub 2018 Jan 19.
• [3] Distinct substrate specificities of human GlcNAc-6-sulfotransferases revealed by mass spectrometry-based sulfoglycomic analysis.J Biol Chem. 2018 Sep 28;293(39):15163-15177. doi: 10.1074/jbc.RA118.001937. Epub 2018 Aug 9.
• [4] Ectopic expression of a GlcNAc 6-O-sulfotransferase, GlcNAc6ST-2, in colonic mucinous adenocarcinoma.Glycobiology. 2002 Jun;12(6):379-88. doi: 10.1093/glycob/12.6.379.
• [5] A HEV-restricted sulfotransferase is expressed in rheumatoid arthritis synovium and is induced by lymphotoxin-alpha/beta and TNF-alpha in cultured endothelial cells.BMC Immunol. 2005 Mar 7;6:6. doi: 10.1186/1471-2172-6-6.
• [6] Ectopic expression of N-acetylglucosamine 6-O-sulfotransferase 2 in chemotherapy-resistant ovarian adenocarcinomas.Glycoconj J. 2006 Jul;23(5-6):453-60. doi: 10.1007/s10719-006-6979-6.
• [7] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [8] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [9] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [10] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [11] Endometrial receptivity is affected in women with high circulating progesterone levels at the end of the follicular phase: a functional genomics analysis. Hum Reprod. 2011 Jul;26(7):1813-25.
• [12] 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.
• [13] 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.
• [14] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [15] 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.
• [16] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.