Details of Drug Off-Target (DOT)

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

• DOT Name: Histone-lysine N-methyltransferase EZH2 (EZH2)
• Synonyms: EC 2.1.1.356; ENX-1; Enhancer of zeste homolog 2; Lysine N-methyltransferase 6
• Gene Name: EZH2
• Related Disease: Weaver syndrome
• UniProt ID: EZH2_HUMAN
• PDB ID: 4MI0; 4MI5; 5GSA; 5H14; 5H15; 5H17; 5H19; 5H24; 5H25; 5HYN; 5IJ7; 5IJ8; 5LS6; 5U5T; 5U62; 5WG6; 5WUK; 6C23; 6C24; 6LO2; 6P5L; 6U4Y; 6WKR; 7AT8; 7QJG; 7QJU; 7QK4; 8FYH
• EC Number: 2.1.1.356
• Pfam ID: PF21358 ; PF11616 ; PF18118 ; PF18264 ; PF00856
• Sequence:
  MGQTGKKSEKGPVCWRKRVKSEYMRLRQLKRFRRADEVKSMFSSNRQKILERTEILNQEW
  KQRRIQPVHILTSVSSLRGTRECSVTSDLDFPTQVIPLKTLNAVASVPIMYSWSPLQQNF
  MVEDETVLHNIPYMGDEVLDQDGTFIEELIKNYDGKVHGDRECGFINDEIFVELVNALGQ
  YNDDDDDDDGDDPEEREEKQKDLEDHRDDKESRPPRKFPSDKIFEAISSMFPDKGTAEEL
  KEKYKELTEQQLPGALPPECTPNIDGPNAKSVQREQSLHSFHTLFCRRCFKYDCFLHPFH
  ATPNTYKRKNTETALDNKPCGPQCYQHLEGAKEFAAALTAERIKTPPKRPGGRRRGRLPN
  NSSRPSTPTINVLESKDTDSDREAGTETGGENNDKEEEEKKDETSSSSEANSRCQTPIKM
  KPNIEPPENVEWSGAEASMFRVLIGTYYDNFCAIARLIGTKTCRQVYEFRVKESSIIAPA
  PAEDVDTPPRKKKRKHRLWAAHCRKIQLKKDGSSNHVYNYQPCDHPRQPCDSSCPCVIAQ
  NFCEKFCQCSSECQNRFPGCRCKAQCNTKQCPCYLAVRECDPDLCLTCGAADHWDSKNVS
  CKNCSIQRGSKKHLLLAPSDVAGWGIFIKDPVQKNEFISEYCGEIISQDEADRRGKVYDK
  YMCSFLFNLNNDFVVDATRKGNKIRFANHSVNPNCYAKVMMVNGDHRIGIFAKRAIQTGE
  ELFFDYRYSQADALKYVGIEREMEIP
• Function: Polycomb group (PcG) protein. Catalytic subunit of the PRC2/EED-EZH2 complex, which methylates 'Lys-9' (H3K9me) and 'Lys-27' (H3K27me) of histone H3, leading to transcriptional repression of the affected target gene. Able to mono-, di- and trimethylate 'Lys-27' of histone H3 to form H3K27me1, H3K27me2 and H3K27me3, respectively. Displays a preference for substrates with less methylation, loses activity when progressively more methyl groups are incorporated into H3K27, H3K27me0 > H3K27me1 > H3K27me2. Compared to EZH1-containing complexes, it is more abundant in embryonic stem cells and plays a major role in forming H3K27me3, which is required for embryonic stem cell identity and proper differentiation. 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, CDKN2A and retinoic acid target genes. EZH2 can also methylate non-histone proteins such as the transcription factor GATA4 and the nuclear receptor RORA. Regulates the circadian clock via histone methylation at the promoter of the circadian genes. Essential for the CRY1/2-mediated repression of the transcriptional activation of PER1/2 by the CLOCK-BMAL1 heterodimer; involved in the di and trimethylation of 'Lys-27' of histone H3 on PER1/2 promoters which is necessary for the CRY1/2 proteins to inhibit transcription.
• Tissue Specificity: In the ovary, expressed in primordial follicles and oocytes and also in external follicle cells (at protein level) . Expressed in many tissues . Overexpressed in numerous tumor types including carcinomas of the breast, colon, larynx, lymphoma and testis .
• KEGG Pathway:
  Lysine degradation (hsa00310)
  Metabolic pathways (hsa01100)
  Polycomb repressive complex (hsa03083)
  MicroR.s in cancer (hsa05206)
• 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)
• BioCyc Pathway: MetaCyc:HS02911-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Weaver syndrome	DIS2CE7R	Definitive	Autosomal dominant	[1]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Topotecan	DMP6G8T	Approved	Histone-lysine N-methyltransferase EZH2 (EZH2) affects the response to substance of Topotecan.	[40]
Resveratrol	DM3RWXL	Phase 3	Histone-lysine N-methyltransferase EZH2 (EZH2) increases the response to substance of Resveratrol.	[41]

39 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 Histone-lysine N-methyltransferase EZH2 (EZH2).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Histone-lysine N-methyltransferase EZH2 (EZH2).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Histone-lysine N-methyltransferase EZH2 (EZH2).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Histone-lysine N-methyltransferase EZH2 (EZH2).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Histone-lysine N-methyltransferase EZH2 (EZH2).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Histone-lysine N-methyltransferase EZH2 (EZH2).	[7]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Histone-lysine N-methyltransferase EZH2 (EZH2).	[8]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Histone-lysine N-methyltransferase EZH2 (EZH2).	[11]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Histone-lysine N-methyltransferase EZH2 (EZH2).	[12]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Histone-lysine N-methyltransferase EZH2 (EZH2).	[13]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Histone-lysine N-methyltransferase EZH2 (EZH2).	[14]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Histone-lysine N-methyltransferase EZH2 (EZH2).	[13]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Histone-lysine N-methyltransferase EZH2 (EZH2).	[14]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Histone-lysine N-methyltransferase EZH2 (EZH2).	[15]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Histone-lysine N-methyltransferase EZH2 (EZH2).	[12]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Histone-lysine N-methyltransferase EZH2 (EZH2).	[16]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of Histone-lysine N-methyltransferase EZH2 (EZH2).	[17]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Histone-lysine N-methyltransferase EZH2 (EZH2).	[18]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Histone-lysine N-methyltransferase EZH2 (EZH2).	[19]
Ethanol	DMDRQZU	Approved	Ethanol decreases the expression of Histone-lysine N-methyltransferase EZH2 (EZH2).	[20]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Histone-lysine N-methyltransferase EZH2 (EZH2).	[21]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of Histone-lysine N-methyltransferase EZH2 (EZH2).	[22]
DTI-015	DMXZRW0	Approved	DTI-015 decreases the expression of Histone-lysine N-methyltransferase EZH2 (EZH2).	[23]
Lucanthone	DMZLBUO	Approved	Lucanthone decreases the expression of Histone-lysine N-methyltransferase EZH2 (EZH2).	[24]
Clorgyline	DMCEUJD	Approved	Clorgyline decreases the expression of Histone-lysine N-methyltransferase EZH2 (EZH2).	[25]
Palbociclib	DMD7L94	Approved	Palbociclib decreases the expression of Histone-lysine N-methyltransferase EZH2 (EZH2).	[26]
Enzalutamide	DMGL19D	Approved	Enzalutamide decreases the expression of Histone-lysine N-methyltransferase EZH2 (EZH2).	[27]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Histone-lysine N-methyltransferase EZH2 (EZH2).	[28]
Triptolide	DMCMDVR	Phase 3	Triptolide decreases the expression of Histone-lysine N-methyltransferase EZH2 (EZH2).	[29]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Histone-lysine N-methyltransferase EZH2 (EZH2).	[30]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Histone-lysine N-methyltransferase EZH2 (EZH2).	[31]
GSK2816126	DMJDVW4	Phase 1	GSK2816126 decreases the activity of Histone-lysine N-methyltransferase EZH2 (EZH2).	[32]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Histone-lysine N-methyltransferase EZH2 (EZH2).	[33]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Histone-lysine N-methyltransferase EZH2 (EZH2).	[34]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Histone-lysine N-methyltransferase EZH2 (EZH2).	[35]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Histone-lysine N-methyltransferase EZH2 (EZH2).	[36]
geraniol	DMS3CBD	Investigative	geraniol decreases the expression of Histone-lysine N-methyltransferase EZH2 (EZH2).	[37]
DZNep	DM0JXBK	Investigative	DZNep decreases the activity of Histone-lysine N-methyltransferase EZH2 (EZH2).	[38]
GSK343	DM9QU5Y	Investigative	GSK343 decreases the activity of Histone-lysine N-methyltransferase EZH2 (EZH2).	[39]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic increases the phosphorylation of Histone-lysine N-methyltransferase EZH2 (EZH2).	[9]
Quercetin	DM3NC4M	Approved	Quercetin decreases the phosphorylation of Histone-lysine N-methyltransferase EZH2 (EZH2).	[10]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Histone-lysine N-methyltransferase EZH2 (EZH2).	[10]

References

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