Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTB1XSSF)

• DOT Name: Chondroitin sulfate synthase 1 (CHSY1)
• Synonyms: EC 2.4.1.175; EC 2.4.1.226; Chondroitin glucuronyltransferase 1; Chondroitin synthase 1; ChSy-1; Glucuronosyl-N-acetylgalactosaminyl-proteoglycan 4-beta-N-acetylgalactosaminyltransferase 1; N-acetylgalactosaminyl-proteoglycan 3-beta-glucuronosyltransferase 1; N-acetylgalactosaminyltransferase 1
• Gene Name: CHSY1
• Related Disease:
  Temtamy preaxial brachydactyly syndrome
  Adult glioblastoma
  B-cell neoplasm
  Brachydactyly
  Colorectal carcinoma
  Congenital deformities of limbs
  Glioblastoma multiforme
  Hepatocellular carcinoma
  Malignant peripheral nerve sheath tumor
  Neoplasm
  Sarcoma
  Soft tissue sarcoma
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Clear cell renal carcinoma
• UniProt ID: CHSS1_HUMAN
• EC Number: 2.4.1.175; 2.4.1.226
• Pfam ID: PF05679
• Sequence:
  MAARGRRAWLSVLLGLVLGFVLASRLVLPRASELKRAGPRRRASPEGCRSGQAAASQAGG
  ARGDARGAQLWPPGSDPDGGPRDRNFLFVGVMTAQKYLQTRAVAAYRTWSKTIPGKVQFF
  SSEGSDTSVPIPVVPLRGVDDSYPPQKKSFMMLKYMHDHYLDKYEWFMRADDDVYIKGDR
  LENFLRSLNSSEPLFLGQTGLGTTEEMGKLALEPGENFCMGGPGVIMSREVLRRMVPHIG
  KCLREMYTTHEDVEVGRCVRRFAGVQCVWSYEMQQLFYENYEQNKKGYIRDLHNSKIHQA
  ITLHPNKNPPYQYRLHSYMLSRKISELRHRTIQLHREIVLMSKYSNTEIHKEDLQLGIPP
  SFMRFQPRQREEILEWEFLTGKYLYSAVDGQPPRRGMDSAQREALDDIVMQVMEMINANA
  KTRGRIIDFKEIQYGYRRVNPMYGAEYILDLLLLYKKHKGKKMTVPVRRHAYLQQTFSKI
  QFVEHEELDAQELAKRINQESGSLSFLSNSLKKLVPFQLPGSKSEHKEPKDKKINILIPL
  SGRFDMFVRFMGNFEKTCLIPNQNVKLVVLLFNSDSNPDKAKQVELMRDYRIKYPKADMQ
  ILPVSGEFSRALALEVGSSQFNNESLLFFCDVDLVFTTEFLQRCRANTVLGQQIYFPIIF
  SQYDPKIVYSGKVPSDNHFAFTQKTGFWRNYGFGITCIYKGDLVRVGGFDVSIQGWGLED
  VDLFNKVVQAGLKTFRSQEVGVVHVHHPVFCDPNLDPKQYKMCLGSKASTYGSTQQLAEM
  WLEKNDPSYSKSSNNNGSVRTA
• Function: Has both beta-1,3-glucuronic acid and beta-1,4-N-acetylgalactosamine transferase activity. Transfers glucuronic acid (GlcUA) from UDP-GlcUA and N-acetylgalactosamine (GalNAc) from UDP-GalNAc to the non-reducing end of the elongating chondroitin polymer. Involved in the negative control of osteogenesis likely through the modulation of NOTCH signaling.
• Tissue Specificity: Ubiquitous, with the highest levels in placenta. Detected at low levels in brain, heart, skeletal muscle, colon, thymus, spleen, kidney, liver, adrenal gland, mammary gland, stomach, small intestine, lung and peripheral blood leukocytes.
• KEGG Pathway:
  Glycosaminoglycan biosynthesis - chondroitin sulfate / dermatan sulfate (hsa00532)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Defective CHSY1 causes TPBS (R-HSA-3595177)
  Chondroitin sulfate biosynthesis (R-HSA-2022870)
• BioCyc Pathway: MetaCyc:HS13400-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Temtamy preaxial brachydactyly syndrome	DISBN663	Definitive	Autosomal recessive	[1]
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[2]
B-cell neoplasm	DISVY326	Strong	Altered Expression	[3]
Brachydactyly	DIS2533F	Strong	Biomarker	[4]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[3]
Congenital deformities of limbs	DISP4N1Q	Strong	Biomarker	[5]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[2]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[6]
Malignant peripheral nerve sheath tumor	DIS0JTN6	Strong	Altered Expression	[7]
Neoplasm	DISZKGEW	Strong	Altered Expression	[7]
Sarcoma	DISZDG3U	Strong	Altered Expression	[7]
Soft tissue sarcoma	DISSN8XB	Strong	Altered Expression	[7]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[3]
Breast cancer	DIS7DPX1	Limited	Biomarker	[8]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[8]
Clear cell renal carcinoma	DISBXRFJ	Limited	Biomarker	[9]

16 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 Chondroitin sulfate synthase 1 (CHSY1).	[10]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Chondroitin sulfate synthase 1 (CHSY1).	[11]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Chondroitin sulfate synthase 1 (CHSY1).	[12]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Chondroitin sulfate synthase 1 (CHSY1).	[13]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Chondroitin sulfate synthase 1 (CHSY1).	[14]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Chondroitin sulfate synthase 1 (CHSY1).	[15]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Chondroitin sulfate synthase 1 (CHSY1).	[16]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Chondroitin sulfate synthase 1 (CHSY1).	[17]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Chondroitin sulfate synthase 1 (CHSY1).	[18]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Chondroitin sulfate synthase 1 (CHSY1).	[19]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Chondroitin sulfate synthase 1 (CHSY1).	[20]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Chondroitin sulfate synthase 1 (CHSY1).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Chondroitin sulfate synthase 1 (CHSY1).	[21]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Chondroitin sulfate synthase 1 (CHSY1).	[23]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Chondroitin sulfate synthase 1 (CHSY1).	[24]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Chondroitin sulfate synthase 1 (CHSY1).	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Chondroitin sulfate synthase 1 (CHSY1).	[22]

References

• [1] A new multiple congenital anomaly, mental retardation syndrome with preaxial brachydactyly, hyperphalangism, deafness and orodental anomalies. Clin Dysmorphol. 1998 Oct;7(4):249-55. doi: 10.1097/00019605-199810000-00003.
• [2] Loss of CHSY1, a secreted FRINGE enzyme, causes syndromic brachydactyly in humans via increased NOTCH signaling. Am J Hum Genet. 2010 Dec 10;87(6):768-78. doi: 10.1016/j.ajhg.2010.11.005.
• [3] CHSY1 promoted proliferation and suppressed apoptosis in colorectal cancer through regulation of the NFB and/or caspase-3/7 signaling pathway.Oncol Lett. 2018 Nov;16(5):6140-6146. doi: 10.3892/ol.2018.9385. Epub 2018 Sep 3.
• [4] Chondroitin sulfate synthase 1 (Chsy1) is required for bone development and digit patterning.Dev Biol. 2012 Mar 15;363(2):413-25. doi: 10.1016/j.ydbio.2012.01.005. Epub 2012 Jan 17.
• [5] Temtamy preaxial brachydactyly syndrome is caused by loss-of-function mutations in chondroitin synthase 1, a potential target of BMP signaling. Am J Hum Genet. 2010 Dec 10;87(6):757-67. doi: 10.1016/j.ajhg.2010.10.003.
• [6] CHSY1 promotes aggressive phenotypes of hepatocellular carcinoma cells via activation of the hedgehog signaling pathway.Cancer Lett. 2017 Sep 10;403:280-288. doi: 10.1016/j.canlet.2017.06.023. Epub 2017 Jun 23.
• [7] Chondroitin sulfate synthase 1 expression is associated with malignant potential of soft tissue sarcomas with myxoid substance.Hum Pathol. 2016 Apr;50:15-23. doi: 10.1016/j.humpath.2015.11.005. Epub 2015 Nov 22.
• [8] Tumor-dependent Effects of Proteoglycans and Various Glycosaminoglycan Synthesizing Enzymes and Sulfotransferases on Patients' Outcome.Curr Cancer Drug Targets. 2019;19(3):210-221. doi: 10.2174/1568009618666180706165845.
• [9] FOXM1-Activated LINC01094 Promotes Clear Cell Renal Cell Carcinoma Development via MicroRNA 224-5p/CHSY1.Mol Cell Biol. 2020 Jan 16;40(3):e00357-19. doi: 10.1128/MCB.00357-19. Print 2020 Jan 16.
• [10] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [11] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [12] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [13] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [14] 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.
• [15] Transcriptomics hit the target: monitoring of ligand-activated and stress response pathways for chemical testing. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):7-18.
• [16] Convergent transcriptional profiles induced by endogenous estrogen and distinct xenoestrogens in breast cancer cells. Carcinogenesis. 2006 Aug;27(8):1567-78.
• [17] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [18] 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.
• [19] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [20] 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.
• [21] 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.
• [22] 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.
• [23] 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.
• [24] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [25] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.