Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTUJ14DW)

• DOT Name: Glypican-4 (GPC4)
• Synonyms: K-glypican
• Gene Name: GPC4
• Related Disease:
  Keipert syndrome
  Adult teratoma
  Advanced cancer
  Bone development disease
  Colorectal carcinoma
  Gastric cancer
  Hydrocephalus
  Non-alcoholic fatty liver disease
  Non-insulin dependent diabetes
  Obesity
  Overgrowth syndrome
  Pancreatic cancer
  Parkinson disease
  Perlman syndrome
  Polydactyly
  Simpson-Golabi-Behmel syndrome
  Teratoma
  Epstein barr virus infection
  Nasopharyngeal carcinoma
  Stomach cancer
  Type-1/2 diabetes
• UniProt ID: GPC4_HUMAN
• Pfam ID: PF01153
• Sequence:
  MARFGLPALLCTLAVLSAALLAAELKSKSCSEVRRLYVSKGFNKNDAPLHEINGDHLKIC
  PQGSTCCSQEMEEKYSLQSKDDFKSVVSEQCNHLQAVFASRYKKFDEFFKELLENAEKSL
  NDMFVKTYGHLYMQNSELFKDLFVELKRYYVVGNVNLEEMLNDFWARLLERMFRLVNSQY
  HFTDEYLECVSKYTEQLKPFGDVPRKLKLQVTRAFVAARTFAQGLAVAGDVVSKVSVVNP
  TAQCTHALLKMIYCSHCRGLVTVKPCYNYCSNIMRGCLANQGDLDFEWNNFIDAMLMVAE
  RLEGPFNIESVMDPIDVKISDAIMNMQDNSVQVSQKVFQGCGPPKPLPAGRISRSISESA
  FSARFRPHHPEERPTTAAGTSLDRLVTDVKEKLKQAKKFWSSLPSNVCNDERMAAGNGNE
  DDCWNGKGKSRYLFAVTGNGLANQGNNPEVQVDTSKPDILILRQIMALRVMTSKMKNAYN
  GNDVDFFDISDESSGEGSGSGCEYQQCPSEFDYNATDHAGKSANEKADSAGVRPGAQAYL
  LTVFCILFLVMQREWR
• Function: Cell surface proteoglycan that bears heparan sulfate. May be involved in the development of kidney tubules and of the central nervous system.
• KEGG Pathway: Wnt sig.ling pathway (hsa04310)
• Reactome Pathway:
  HS-GAG biosynthesis (R-HSA-2022928)
  HS-GAG degradation (R-HSA-2024096)
  Defective B4GALT7 causes EDS, progeroid type (R-HSA-3560783)
  Defective B3GAT3 causes JDSSDHD (R-HSA-3560801)
  Defective EXT2 causes exostoses 2 (R-HSA-3656237)
  Defective EXT1 causes exostoses 1, TRPS2 and CHDS (R-HSA-3656253)
  Defective B3GALT6 causes EDSP2 and SEMDJL1 (R-HSA-4420332)
  Attachment and Entry (R-HSA-9694614)
  Retinoid metabolism and transport (R-HSA-975634)
  A tetrasaccharide linker sequence is required for GAG synthesis (R-HSA-1971475)

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Keipert syndrome	DISJ7D7I	Definitive	X-linked recessive	[1]
Adult teratoma	DISBY81U	Strong	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[3]
Bone development disease	DISVKAZS	Strong	Biomarker	[1]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[4]
Gastric cancer	DISXGOUK	Strong	Genetic Variation	[5]
Hydrocephalus	DISIZUF7	Strong	Genetic Variation	[6]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Genetic Variation	[7]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[7]
Obesity	DIS47Y1K	Strong	Altered Expression	[8]
Overgrowth syndrome	DISHK54G	Strong	Biomarker	[9]
Pancreatic cancer	DISJC981	Strong	Biomarker	[3]
Parkinson disease	DISQVHKL	Strong	Biomarker	[2]
Perlman syndrome	DISN3KMO	Strong	Genetic Variation	[10]
Polydactyly	DIS25BMZ	Strong	Biomarker	[9]
Simpson-Golabi-Behmel syndrome	DIS9H9TY	Strong	Genetic Variation	[11]
Teratoma	DIS6ICY4	Strong	Biomarker	[2]
Epstein barr virus infection	DISOO0WT	Limited	Genetic Variation	[12]
Nasopharyngeal carcinoma	DISAOTQ0	Limited	Genetic Variation	[12]
Stomach cancer	DISKIJSX	Limited	Genetic Variation	[12]
Type-1/2 diabetes	DISIUHAP	Limited	Biomarker	[13]

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 Glypican-4 (GPC4).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Glypican-4 (GPC4).	[27]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Glypican-4 (GPC4).	[29]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Glypican-4 (GPC4).	[15]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Glypican-4 (GPC4).	[16]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Glypican-4 (GPC4).	[17]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Glypican-4 (GPC4).	[18]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Glypican-4 (GPC4).	[19]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Glypican-4 (GPC4).	[20]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Glypican-4 (GPC4).	[21]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Glypican-4 (GPC4).	[22]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Glypican-4 (GPC4).	[23]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Glypican-4 (GPC4).	[24]
Dasatinib	DMJV2EK	Approved	Dasatinib increases the expression of Glypican-4 (GPC4).	[25]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Glypican-4 (GPC4).	[26]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Glypican-4 (GPC4).	[28]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Glypican-4 (GPC4).	[30]

References

• [1] Pathogenic Variants in GPC4 Cause Keipert Syndrome. Am J Hum Genet. 2019 May 2;104(5):914-924. doi: 10.1016/j.ajhg.2019.02.026. Epub 2019 Apr 11.
• [2] Reducing glypican-4 in ES cells improves recovery in a rat model of Parkinson's disease by increasing the production of dopaminergic neurons and decreasing teratoma formation.J Neurosci. 2014 Jun 11;34(24):8318-23. doi: 10.1523/JNEUROSCI.2501-13.2014.
• [3] Targeting glypican-4 overcomes 5-FU resistance and attenuates stem cell-like properties via suppression of Wnt/-catenin pathway in pancreatic cancer cells.J Cell Biochem. 2018 Nov;119(11):9498-9512. doi: 10.1002/jcb.27266. Epub 2018 Jul 16.
• [4] CD36 inhibits -catenin/c-myc-mediated glycolysis through ubiquitination of GPC4 to repress colorectal tumorigenesis.Nat Commun. 2019 Sep 4;10(1):3981. doi: 10.1038/s41467-019-11662-3.
• [5] Glypican-4 gene polymorphism (rs1048369) and susceptibility to Epstein-Barr virus-associated and -negative gastric carcinoma.Virus Res. 2016 Jul 15;220:52-6. doi: 10.1016/j.virusres.2016.04.005. Epub 2016 Apr 9.
• [6] Glypican 3 and glypican 4 are juxtaposed in Xq26.1.Gene. 1998 Dec 28;225(1-2):9-16. doi: 10.1016/s0378-1119(98)00549-6.
• [7] Glypican-4 is increased in human subjects with impaired glucose tolerance and decreased in patients with newly diagnosed type 2 diabetes.Acta Diabetol. 2014 Dec;51(6):981-90. doi: 10.1007/s00592-014-0652-5. Epub 2014 Sep 21.
• [8] Serum glypican 4 level in obese children and its relation to degree of obesity.Clin Endocrinol (Oxf). 2017 Dec;87(6):689-695. doi: 10.1111/cen.13435. Epub 2017 Aug 22.
• [9] An interstitial duplication of chromosome 13q31.3q32.1 further delineates the critical region for postaxial polydactyly type A2.Eur J Med Genet. 2010 Jan-Feb;53(1):45-9. doi: 10.1016/j.ejmg.2009.11.003. Epub 2009 Nov 23.
• [10] Mutational analysis of the GPC3/GPC4 glypican gene cluster on Xq26 in patients with Simpson-Golabi-Behmel syndrome: identification of loss-of-function mutations in the GPC3 gene. Hum Mol Genet. 2000 May 22;9(9):1321-8. doi: 10.1093/hmg/9.9.1321.
• [11] Xq26 duplications lead to undergrowth or overgrowth via competing pathways including GPC3/GPC4.Ann Hum Genet. 2020 Mar;84(2):201-204. doi: 10.1111/ahg.12357. Epub 2019 Oct 3.
• [12] The Glypican-4 Gene Polymorphism rs1048369 and Susceptibility to Epstein-Barr Virus-Positive and -Negative Nasopharyngeal Carcinoma in Northern China.Oncol Res Treat. 2019;42(11):572-579. doi: 10.1159/000502753. Epub 2019 Sep 13.
• [13] The response of serum Glypican-4 levels and its potential regulatory mechanism to endurance training and chamomile flowers' hydroethanolic extract in streptozotocin-nicotinamide-induced diabetic rats.Acta Diabetol. 2018 Sep;55(9):935-942. doi: 10.1007/s00592-018-1173-4. Epub 2018 Jun 13.
• [14] 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.
• [15] Cyclosporine A--induced oxidative stress in human renal mesangial cells: a role for ERK 1/2 MAPK signaling. Toxicol Sci. 2012 Mar;126(1):101-13.
• [16] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [17] 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.
• [18] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [19] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [20] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [21] Global effects of inorganic arsenic on gene expression profile in human macrophages. Mol Immunol. 2009 Feb;46(4):649-56.
• [22] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [23] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [24] 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.
• [25] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [26] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [27] 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.
• [28] 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.
• [29] Expression and DNA methylation changes in human breast epithelial cells after bisphenol A exposure. Int J Oncol. 2012 Jul;41(1):369-77.
• [30] 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.