Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTC4DWB6)

• DOT Name: Histone-lysine N-methyltransferase EHMT2 (EHMT2)
• Synonyms: EC 2.1.1.-; EC 2.1.1.367; Euchromatic histone-lysine N-methyltransferase 2; HLA-B-associated transcript 8; Histone H3-K9 methyltransferase 3; H3-K9-HMTase 3; Lysine N-methyltransferase 1C; Protein G9a
• Gene Name: EHMT2
• UniProt ID: EHMT2_HUMAN
• PDB ID: 2O8J; 3DM1; 3K5K; 3RJW; 4NVQ; 5JHN; 5JIN; 5JIY; 5JJ0; 5T0K; 5T0M; 5TTF; 5TUY; 5V9I; 5VSC; 5VSE; 6MM1; 7BTV; 7BUC; 7DCF; 7T7L; 7X73; 7XUA; 7XUB; 7XUC; 7XUD
• EC Number: 2.1.1.-; 2.1.1.367
• Pfam ID: PF00023 ; PF12796 ; PF21533 ; PF05033 ; PF00856
• Sequence:
  MAAAAGAAAAAAAEGEAPAEMGALLLEKETRGATERVHGSLGDTPRSEETLPKATPDSLE
  PAGPSSPASVTVTVGDEGADTPVGATPLIGDESENLEGDGDLRGGRILLGHATKSFPSSP
  SKGGSCPSRAKMSMTGAGKSPPSVQSLAMRLLSMPGAQGAAAAGSEPPPATTSPEGQPKV
  HRARKTMSKPGNGQPPVPEKRPPEIQHFRMSDDVHSLGKVTSDLAKRRKLNSGGGLSEEL
  GSARRSGEVTLTKGDPGSLEEWETVVGDDFSLYYDSYSVDERVDSDSKSEVEALTEQLSE
  EEEEEEEEEEEEEEEEEEEEEEEDEESGNQSDRSGSSGRRKAKKKWRKDSPWVKPSRKRR
  KREPPRAKEPRGVNGVGSSGPSEYMEVPLGSLELPSEGTLSPNHAGVSNDTSSLETERGF
  EELPLCSCRMEAPKIDRISERAGHKCMATESVDGELSGCNAAILKRETMRPSSRVALMVL
  CETHRARMVKHHCCPGCGYFCTAGTFLECHPDFRVAHRFHKACVSQLNGMVFCPHCGEDA
  SEAQEVTIPRGDGVTPPAGTAAPAPPPLSQDVPGRADTSQPSARMRGHGEPRRPPCDPLA
  DTIDSSGPSLTLPNGGCLSAVGLPLGPGREALEKALVIQESERRKKLRFHPRQLYLSVKQ
  GELQKVILMLLDNLDPNFQSDQQSKRTPLHAAAQKGSVEICHVLLQAGANINAVDKQQRT
  PLMEAVVNNHLEVARYMVQRGGCVYSKEEDGSTCLHHAAKIGNLEMVSLLLSTGQVDVNA
  QDSGGWTPIIWAAEHKHIEVIRMLLTRGADVTLTDNEENICLHWASFTGSAAIAEVLLNA
  RCDLHAVNYHGDTPLHIAARESYHDCVLLFLSRGANPELRNKEGDTAWDLTPERSDVWFA
  LQLNRKLRLGVGNRAIRTEKIICRDVARGYENVPIPCVNGVDGEPCPEDYKYISENCETS
  TMNIDRNITHLQHCTCVDDCSSSNCLCGQLSIRCWYDKDGRLLQEFNKIEPPLIFECNQA
  CSCWRNCKNRVVQSGIKVRLQLYRTAKMGWGVRALQTIPQGTFICEYVGELISDAEADVR
  EDDSYLFDLDNKDGEVYCIDARYYGNISRFINHLCDPNIIPVRVFMLHQDLRFPRIAFFS
  SRDIRTGEELGFDYGDRFWDIKSKYFTCQCGSEKCKHSAEAIALEQSRLARLDPHPELLP
  ELGSLPPVNT
• Function: Histone methyltransferase that specifically mono- and dimethylates 'Lys-9' of histone H3 (H3K9me1 and H3K9me2, respectively) in euchromatin. H3K9me represents a specific tag for epigenetic transcriptional repression by recruiting HP1 proteins to methylated histones. Also mediates monomethylation of 'Lys-56' of histone H3 (H3K56me1) in G1 phase, leading to promote interaction between histone H3 and PCNA and regulating DNA replication. Also weakly methylates 'Lys-27' of histone H3 (H3K27me). Also required for DNA methylation, the histone methyltransferase activity is not required for DNA methylation, suggesting that these 2 activities function independently. Probably targeted to histone H3 by different DNA-binding proteins like E2F6, MGA, MAX and/or DP1. May also methylate histone H1. In addition to the histone methyltransferase activity, also methylates non-histone proteins: mediates dimethylation of 'Lys-373' of p53/TP53. Also methylates CDYL, WIZ, ACIN1, DNMT1, HDAC1, ERCC6, KLF12 and itself. Recruited to the promoters of target genes through interaction with transcriptional repressor MSX1, leading to the inhibition of myoblast differentiation via transcriptional repression of differentiation factors.
• Tissue Specificity: Expressed in all tissues examined, with high levels in fetal liver, thymus, lymph node, spleen and peripheral blood leukocytes and lower level in bone marrow.
• KEGG Pathway:
  Lysine degradation (hsa00310)
  Metabolic pathways (hsa01100)
  Longevity regulating pathway (hsa04211)
• Reactome Pathway:
  PKMTs methylate histone lysines (R-HSA-3214841)
  ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression (R-HSA-427389)
  Regulation of TP53 Activity through Methylation (R-HSA-6804760)
  RNA Polymerase I Transcription Initiation (R-HSA-73762)
  Transcriptional Regulation by VENTX (R-HSA-8853884)
  Transcriptional Regulation by E2F6 (R-HSA-8953750)
  Senescence-Associated Secretory Phenotype (SASP) (R-HSA-2559582)
• BioCyc Pathway: MetaCyc:HS06313-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Decitabine	DMQL8XJ	Approved	Histone-lysine N-methyltransferase EHMT2 (EHMT2) affects the response to substance of Decitabine.	[22]

6 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 Histone-lysine N-methyltransferase EHMT2 (EHMT2).	[1]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Histone-lysine N-methyltransferase EHMT2 (EHMT2).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Histone-lysine N-methyltransferase EHMT2 (EHMT2).	[18]
TAK-243	DM4GKV2	Phase 1	TAK-243 affects the sumoylation of Histone-lysine N-methyltransferase EHMT2 (EHMT2).	[19]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Histone-lysine N-methyltransferase EHMT2 (EHMT2).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Histone-lysine N-methyltransferase EHMT2 (EHMT2).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Histone-lysine N-methyltransferase EHMT2 (EHMT2).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Histone-lysine N-methyltransferase EHMT2 (EHMT2).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Histone-lysine N-methyltransferase EHMT2 (EHMT2).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Histone-lysine N-methyltransferase EHMT2 (EHMT2).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Histone-lysine N-methyltransferase EHMT2 (EHMT2).	[6]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Histone-lysine N-methyltransferase EHMT2 (EHMT2).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Histone-lysine N-methyltransferase EHMT2 (EHMT2).	[8]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Histone-lysine N-methyltransferase EHMT2 (EHMT2).	[10]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Histone-lysine N-methyltransferase EHMT2 (EHMT2).	[11]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Histone-lysine N-methyltransferase EHMT2 (EHMT2).	[12]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of Histone-lysine N-methyltransferase EHMT2 (EHMT2).	[13]
Aspirin	DM672AH	Approved	Aspirin increases the expression of Histone-lysine N-methyltransferase EHMT2 (EHMT2).	[14]
Sulindac	DM2QHZU	Approved	Sulindac decreases the expression of Histone-lysine N-methyltransferase EHMT2 (EHMT2).	[14]
Nitric Oxide	DM1RBYG	Approved	Nitric Oxide decreases the expression of Histone-lysine N-methyltransferase EHMT2 (EHMT2).	[15]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Histone-lysine N-methyltransferase EHMT2 (EHMT2).	[16]
Ym155	DM5Q1W4	Phase 2	Ym155 decreases the expression of Histone-lysine N-methyltransferase EHMT2 (EHMT2).	[17]

References

• [1] 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.
• [2] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [3] 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.
• [4] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [5] 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.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Genome-Wide Analysis of Low Dose Bisphenol-A (BPA) Exposure in Human Prostate Cells. Curr Genomics. 2019 May;20(4):260-274. doi: 10.2174/1389202920666190603123040.
• [8] 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.
• [9] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [10] Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells. Toxicol Appl Pharmacol. 2012 Jun 1;261(2):204-16.
• [11] 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.
• [12] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [13] In vitro hydroquinone-induced instauration of histone bivalent mark on human retroelements (LINE-1) in HL60 cells. Toxicol In Vitro. 2017 Apr;40:1-10. doi: 10.1016/j.tiv.2016.12.007. Epub 2016 Dec 13.
• [14] Expression profile analysis of colon cancer cells in response to sulindac or aspirin. Biochem Biophys Res Commun. 2002 Mar 29;292(2):498-512.
• [15] Nitric oxide modifies global histone methylation by inhibiting Jumonji C domain-containing demethylases. J Biol Chem. 2013 May 31;288(22):16004-15. doi: 10.1074/jbc.M112.432294. Epub 2013 Apr 1.
• [16] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [17] YM155 as an inhibitor of cancer stemness simultaneously inhibits autophosphorylation of epidermal growth factor receptor and G9a-mediated stemness in lung cancer cells. PLoS One. 2017 Aug 7;12(8):e0182149. doi: 10.1371/journal.pone.0182149. eCollection 2017.
• [18] 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.
• [19] 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.
• [20] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [21] 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.
• [22] Distinct roles for histone methyltransferases G9a and GLP in cancer germ-line antigen gene regulation in human cancer cells and murine embryonic stem cells. Mol Cancer Res. 2009 Jun;7(6):851-62. doi: 10.1158/1541-7786.MCR-08-0497. Epub 2009 Jun 16.