Details of Drug Off-Target (DOT)

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

• DOT Name: Polycomb protein EED (EED)
• Synonyms: hEED; Embryonic ectoderm development protein; WD protein associating with integrin cytoplasmic tails 1; WAIT-1
• Gene Name: EED
• Related Disease:
  Cohen-Gibson syndrome
  Weaver syndrome
• UniProt ID: EED_HUMAN
• PDB ID: 3IIW ; 3IIY ; 3IJ0 ; 3IJ1 ; 3IJC ; 3JPX ; 3JZG ; 3JZH ; 3JZN ; 3K26 ; 3K27 ; 4W2R ; 4X3E ; 5GSA ; 5H13 ; 5H14 ; 5H15 ; 5H17 ; 5H19 ; 5H24 ; 5H25 ; 5HYN ; 5IJ7 ; 5IJ8 ; 5K0M ; 5LS6 ; 5TTW ; 5U5H ; 5U5K ; 5U5T ; 5U62 ; 5U69 ; 5U6D ; 5U8A ; 5U8F ; 5WG6 ; 5WP3 ; 5WUK ; 6B3W ; 6C23 ; 6C24 ; 6LO2 ; 6SFB ; 6SFC ; 6U4Y ; 6V3X ; 6V3Y ; 6W7F ; 6W7G ; 6WKR ; 6YVI ; 6YVJ ; 7KSO ; 7KSR ; 7KTP ; 7KXT ; 7MSB ; 7MSD ; 7P3C ; 7P3G ; 7P3J ; 7QJG ; 7QJU ; 7QK4 ; 7SI4 ; 7SI5 ; 7TD5 ; 8FYH
• Pfam ID: PF00400
• Sequence:
  MSEREVSTAPAGTDMPAAKKQKLSSDENSNPDLSGDENDDAVSIESGTNTERPDTPTNTP
  NAPGRKSWGKGKWKSKKCKYSFKCVNSLKEDHNQPLFGVQFNWHSKEGDPLVFATVGSNR
  VTLYECHSQGEIRLLQSYVDADADENFYTCAWTYDSNTSHPLLAVAGSRGIIRIINPITM
  QCIKHYVGHGNAINELKFHPRDPNLLLSVSKDHALRLWNIQTDTLVAIFGGVEGHRDEVL
  SADYDLLGEKIMSCGMDHSLKLWRINSKRMMNAIKESYDYNPNKTNRPFISQKIHFPDFS
  TRDIHRNYVDCVRWLGDLILSKSCENAIVCWKPGKMEDDIDKIKPSESNVTILGRFDYSQ
  CDIWYMRFSMDFWQKMLALGNQVGKLYVWDLEVEDPHKAKCTTLTHHKCGAAIRQTSFSR
  DSSILIAVCDDASIWRWDRLR
• Function: Polycomb group (PcG) protein. Component of the PRC2/EED-EZH2 complex, which methylates 'Lys-9' and 'Lys-27' of histone H3, leading to transcriptional repression of the affected target gene. Also recognizes 'Lys-26' trimethylated histone H1 with the effect of inhibiting PRC2 complex methyltransferase activity on nucleosomal histone H3 'Lys-27', whereas H3 'Lys-27' recognition has the opposite effect, enabling the propagation of this repressive mark. The PRC2/EED-EZH2 complex may also serve as a recruiting platform for DNA methyltransferases, thereby linking two epigenetic repression systems. Genes repressed by the PRC2/EED-EZH2 complex include HOXC8, HOXA9, MYT1 and CDKN2A.
• Tissue Specificity: Expressed in brain, colon, heart, kidney, liver, lung, muscle, ovary, peripheral blood leukocytes, pancreas, placenta, prostate, spleen, small intestine, testis, thymus and uterus. Appears to be overexpressed in breast and colon cancer.
• KEGG Pathway: Polycomb repressive complex (hsa03083)
• Reactome Pathway:
  Oxidative Stress Induced Senescence (R-HSA-2559580)
  PKMTs methylate histone lysines (R-HSA-3214841)
  Activation of anterior HOX genes in hindbrain development during early embryogenesis (R-HSA-5617472)
  Regulation of PTEN gene transcription (R-HSA-8943724)
  Transcriptional Regulation by E2F6 (R-HSA-8953750)
  HCMV Early Events (R-HSA-9609690)
  Defective pyroptosis (R-HSA-9710421)
  PRC2 methylates histones and DNA (R-HSA-212300)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cohen-Gibson syndrome	DISSFPR0	Strong	Autosomal dominant	[1]
Weaver syndrome	DIS2CE7R	Supportive	Autosomal dominant	[2]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	Polycomb protein EED (EED) affects the response to substance of Methotrexate.	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Polycomb protein EED (EED).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Polycomb protein EED (EED).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Polycomb protein EED (EED).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Polycomb protein EED (EED).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Polycomb protein EED (EED).	[7]
Enzalutamide	DMGL19D	Approved	Enzalutamide decreases the expression of Polycomb protein EED (EED).	[8]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Polycomb protein EED (EED).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Polycomb protein EED (EED).	[10]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Polycomb protein EED (EED).	[11]
GSK2816126	DMJDVW4	Phase 1	GSK2816126 decreases the expression of Polycomb protein EED (EED).	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Polycomb protein EED (EED).	[13]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Polycomb protein EED (EED).	[14]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Polycomb protein EED (EED).	[15]
OXYQUINOLINE	DMZVS9Y	Investigative	OXYQUINOLINE decreases the expression of Polycomb protein EED (EED).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Polycomb protein EED (EED).	[12]

References

• [1] A novel mutation in EED associated with overgrowth. J Hum Genet. 2015 Jun;60(6):339-42. doi: 10.1038/jhg.2015.26. Epub 2015 Mar 19.
• [2] Novel EED mutation in patient with Weaver syndrome. Am J Med Genet A. 2017 Feb;173(2):541-545. doi: 10.1002/ajmg.a.38055. Epub 2016 Nov 21.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [5] 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.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] 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.
• [8] Dual targeting of EZH2 and androgen receptor as a novel therapy for castration-resistant prostate cancer. Toxicol Appl Pharmacol. 2020 Oct 1;404:115200. doi: 10.1016/j.taap.2020.115200. Epub 2020 Aug 14.
• [9] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [10] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [11] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [12] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [13] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [14] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [15] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [16] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [17] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.