Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTVQ75NX)

• DOT Name: E1A-binding protein p400 (EP400)
• Synonyms: EC 3.6.4.-; CAG repeat protein 32; Domino homolog; hDomino; Trinucleotide repeat-containing gene 12 protein; p400 kDa SWI2/SNF2-related protein
• Gene Name: EP400
• Related Disease:
  Acute myelogenous leukaemia
  Advanced cancer
  Carcinoma
  Chronic hepatitis B virus infection
  Clear cell renal carcinoma
  Hepatocellular carcinoma
  Multiple sclerosis
  Neoplasm
  Peripheral neuropathy
  Renal cell carcinoma
  Retinoblastoma
  Colorectal carcinoma
• UniProt ID: EP400_HUMAN
• EC Number: 3.6.4.-
• Pfam ID: PF15790 ; PF00271 ; PF07529 ; PF00176
• Sequence:
  MHHGTGPQNVQHQLQRSRACPGSEGEEQPAHPNPPPSPAAPFAPSASPSAPQSPSYQIQQ
  LMNRSPATGQNVNITLQSVGPVVGGNQQITLAPLPLPSPTSPGFQFSAQPRRFEHGSPSY
  IQVTSPLSQQVQTQSPTQPSPGPGQALQNVRAGAPGPGLGLCSSSPTGGFVDASVLVRQI
  SLSPSSGGHFVFQDGSGLTQIAQGAQVQLQHPGTPITVRERRPSQPHTQSGGTIHHLGPQ
  SPAAAGGAGLQPLASPSHITTANLPPQISSIIQGQLVQQQQVLQGPPLPRPLGFERTPGV
  LLPGAGGAAGFGMTSPPPPTSPSRTAVPPGLSSLPLTSVGNTGMKKVPKKLEEIPPASPE
  MAQMRKQCLDYHYQEMQALKEVFKEYLIELFFLQHFQGNMMDFLAFKKKHYAPLQAYLRQ
  NDLDIEEEEEEEEEEEEKSEVINDEVKVVTGKDGQTGTPVAIATQLPPKVSAAFSSQQQP
  FQQALAGSLVAGAGSTVETDLFKRQQAMPSTGMAEQSKRPRLEVGHQGVVFQHPGADAGV
  PLQQLMPTAQGGMPPTPQAAQLAGQRQSQQQYDPSTGPPVQNAASLHTPLPQLPGRLPPA
  GVPTAALSSALQFAQQPQVVEAQTQLQIPVKTQQPNVPIPAPPSSQLPIPPSQPAQLALH
  VPTPGKVQVQASQLSSLPQMVASTRLPVDPAPPCPRPLPTSSTSSLAPVSGSGPGPSPAR
  SSPVNRPSSATNKALSPVTSRTPGVVASAPTKPQSPAQNATSSQDSSQDTLTEQITLENQ
  VHQRIAELRKAGLWSQRRLPKLQEAPRPKSHWDYLLEEMQWMATDFAQERRWKVAAAKKL
  VRTVVRHHEEKQLREERGKKEEQSRLRRIAASTAREIECFWSNIEQVVEIKLRVELEEKR
  KKALNLQKVSRRGKELRPKGFDALQESSLDSGMSGRKRKASISLTDDEVDDEEETIEEEE
  ANEGVVDHQTELSNLAKEAELPLLDLMKLYEGAFLPSSQWPRPKPDGEDTSGEEDADDCP
  GDRESRKDLVLIDSLFIMDQFKAAERMNIGKPNAKDIADVTAVAEAILPKGSARVTTSVK
  FNAPSLLYGALRDYQKIGLDWLAKLYRKNLNGILADEAGLGKTVQIIAFFAHLACNEGNW
  GPHLVVVRSCNILKWELELKRWCPGLKILSYIGSHRELKAKRQEWAEPNSFHVCITSYTQ
  FFRGLTAFTRVRWKCLVIDEMQRVKGMTERHWEAVFTLQSQQRLLLIDSPLHNTFLELWT
  MVHFLVPGISRPYLSSPLRAPSEESQDYYHKVVIRLHRVTQPFILRRTKRDVEKQLTKKY
  EHVLKCRLSNRQKALYEDVILQPGTQEALKSGHFVNVLSILVRLQRICNHPGLVEPRHPG
  SSYVAGPLEYPSASLILKALERDFWKEADLSMFDLIGLENKITRHEAELLSKKKIPRKLM
  EEISTSAAPAARPAAAKLKASRLFQPVQYGQKPEGRTVAFPSTHPPRTAAPTTASAAPQG
  PLRGRPPIATFSANPEAKAAAAPFQTSQASASAPRHQPASASSTAASPAHPAKLRAQTTA
  QASTPGQPPPQPQAPSHAAGQSALPQRLVLPSQAQARLPSGEVVKIAQLASITGPQSRVA
  QPETPVTLQFQGSKFTLSHSQLRQLTAGQPLQLQGSVLQIVSAPGQPYLRAPGPVVMQTV
  SQAGAVHGALGSKPPAGGPSPAPLTPQVGVPGRVAVNALAVGEPGTASKPASPIGGPTQE
  EKTRLLKERLDQIYLVNERRCSQAPVYGRDLLRICALPSHGRVQWRGSLDGRRGKEAGPA
  HSYTSSSESPSELMLTLCRCGESLQDVIDRVAFVIPPVVAAPPSLRVPRPPPLYSHRMRI
  LRQGLREHAAPYFQQLRQTTAPRLLQFPELRLVQFDSGKLEALAILLQKLKSEGRRVLIL
  SQMILMLDILEMFLNFHYLTYVRIDENASSEQRQELMRSFNRDRRIFCAILSTHSRTTGI
  NLVEADTVVFYDNDLNPVMDAKAQEWCDRIGRCKDIHIYRLVSGNSIEEKLLKNGTKDLI
  REVAAQGNDYSMAFLTQRTIQELFEVYSPMDDAGFPVKAEEFVVLSQEPSVTETIAPKIA
  RPFIEALKSIEYLEEDAQKSAQEGVLGPHTDALSSDSENMPCDEEPSQLEELADFMEQLT
  PIEKYALNYLELFHTSIEQEKERNSEDAVMTAVRAWEFWNLKTLQEREARLRLEQEEAEL
  LTYTREDAYSMEYVYEDVDGQTEVMPLWTPPTPPQDDSDIYLDSVMCLMYEATPIPEAKL
  PPVYVRKERKRHKTDPSAAGRKKKQRHGEAVVPPRSLFDRATPGLLKIRREGKEQKKNIL
  LKQQVPFAKPLPTFAKPTAEPGQDNPEWLISEDWALLQAVKQLLELPLNLTIVSPAHTPN
  WDLVSDVVNSCSRIYRSSKQCRNRYENVIIPREEGKSKNNRPLRTSQIYAQDENATHTQL
  YTSHFDLMKMTAGKRSPPIKPLLGMNPFQKNPKHASVLAESGINYDKPLPPIQVASLRAE
  RIAKEKKALADQQKAQQPAVAQPPPPQPQPPPPPQQPPPPLPQPQAAGSQPPAGPPAVQP
  QPQPQPQTQPQPVQAPAKAQPAITTGGSAAVLAGTIKTSVTGTSMPTGAVSGNVIVNTIA
  GVPAATFQSINKRLASPVAPGALTTPGGSAPAQVVHTQPPPRAVGSPATATPDLVSMATT
  QGVRAVTSVTASAVVTTNLTPVQTPARSLVPQVSQATGVQLPGKTITPAHFQLLRQQQQQ
  QQQQQQQQQQQQQQQQQQQQQQQQTTTTSQVQVPQIQGQAQSPAQIKAVGKLTPEHLIKM
  QKQKLQMPPQPPPPQAQSAPPQPTAQVQVQTSQPPQQQSPQLTTVTAPRPGALLTGTTVA
  NLQVARLTRVPTSQLQAQGQMQTQAPQPAQVALAKPPVVSVPAAVVSSPGVTTLPMNVAG
  ISVAIGQPQKAAGQTVVAQPVHMQQLLKLKQQAVQQQKAIQPQAAQGPAAVQQKITAQQI
  TTPGAQQKVAYAAQPALKTQFLTTPISQAQKLAGAQQVQTQIQVAKLPQVVQQQTPVASI
  QQVASASQQASPQTVALTQATAAGQQVQMIPAVTATAQVVQQKLIQQQVVTTASAPLQTP
  GAPNPAQVPASSDSPSQQPKLQMRVPAVRLKTPTKPPCQ
• Function: Component of the NuA4 histone acetyltransferase complex which is involved in transcriptional activation of select genes principally by acetylation of nucleosomal histones H4 and H2A. This modification may both alter nucleosome - DNA interactions and promote interaction of the modified histones with other proteins which positively regulate transcription. May be required for transcriptional activation of E2F1 and MYC target genes during cellular proliferation. The NuA4 complex ATPase and helicase activities seem to be, at least in part, contributed by the association of RUVBL1 and RUVBL2 with EP400. May regulate ZNF42 transcription activity. Component of a SWR1-like complex that specifically mediates the removal of histone H2A.Z/H2AZ1 from the nucleosome.
• Tissue Specificity: Ubiquitously expressed.
• KEGG Pathway: ATP-dependent chromatin remodeling (hsa03082)
• Reactome Pathway:
  DNA Damage/Telomere Stress Induced Senescence (R-HSA-2559586)
  HATs acetylate histones (R-HSA-3214847)
  Formation of Senescence-Associated Heterochromatin Foci (SAHF) (R-HSA-2559584)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Carcinoma	DISH9F1N	Strong	Altered Expression	[3]
Chronic hepatitis B virus infection	DISHL4NT	Strong	Genetic Variation	[4]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[3]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[4]
Multiple sclerosis	DISB2WZI	Strong	Altered Expression	[5]
Neoplasm	DISZKGEW	Strong	Altered Expression	[3]
Peripheral neuropathy	DIS7KN5G	Strong	Biomarker	[6]
Renal cell carcinoma	DISQZ2X8	Strong	Altered Expression	[3]
Retinoblastoma	DISVPNPB	Strong	Biomarker	[7]
Colorectal carcinoma	DIS5PYL0	Limited	Altered Expression	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the methylation of E1A-binding protein p400 (EP400).	[9]
Quercetin	DM3NC4M	Approved	Quercetin increases the phosphorylation of E1A-binding protein p400 (EP400).	[13]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of E1A-binding protein p400 (EP400).	[16]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of E1A-binding protein p400 (EP400).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of E1A-binding protein p400 (EP400).	[19]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of E1A-binding protein p400 (EP400).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of E1A-binding protein p400 (EP400).	[10]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of E1A-binding protein p400 (EP400).	[11]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of E1A-binding protein p400 (EP400).	[12]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of E1A-binding protein p400 (EP400).	[14]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of E1A-binding protein p400 (EP400).	[11]
Cidofovir	DMA13GD	Approved	Cidofovir decreases the expression of E1A-binding protein p400 (EP400).	[11]
Ifosfamide	DMCT3I8	Approved	Ifosfamide decreases the expression of E1A-binding protein p400 (EP400).	[11]
Clodronate	DM9Y6X7	Approved	Clodronate decreases the expression of E1A-binding protein p400 (EP400).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of E1A-binding protein p400 (EP400).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of E1A-binding protein p400 (EP400).	[17]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of E1A-binding protein p400 (EP400).	[18]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of E1A-binding protein p400 (EP400).	[20]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of E1A-binding protein p400 (EP400).	[21]

References

• [1] Enhancers of Polycomb EPC1 and EPC2 sustain the oncogenic potential of MLL leukemia stem cells.Leukemia. 2014 May;28(5):1081-91. doi: 10.1038/leu.2013.316. Epub 2013 Oct 29.
• [2] Ossifying fibromyxoid tumor: morphology, genetics, and differential diagnosis.Ann Diagn Pathol. 2016 Feb;20:52-8. doi: 10.1016/j.anndiagpath.2015.11.002. Epub 2015 Dec 2.
• [3] Senescence-associated protein p400 is a prognostic marker in renal cell carcinoma.Oncol Rep. 2013 Nov;30(5):2245-53. doi: 10.3892/or.2013.2698. Epub 2013 Aug 26.
• [4] A blood-based three-gene signature for the non-invasive detection of early human hepatocellular carcinoma.Eur J Cancer. 2014 Mar;50(5):928-36. doi: 10.1016/j.ejca.2013.11.026. Epub 2013 Dec 11.
• [5] Chromatin remodeler Ep400 ensures oligodendrocyte survival and is required for myelination in the vertebrate central nervous system.Nucleic Acids Res. 2019 Jul 9;47(12):6208-6224. doi: 10.1093/nar/gkz376.
• [6] Ep400 deficiency in Schwann cells causes persistent expression of early developmental regulators and peripheral neuropathy.Nat Commun. 2019 May 29;10(1):2361. doi: 10.1038/s41467-019-10287-w.
• [7] Adenoviral E1A function through Myc.Cancer Res. 2009 Jan 1;69(1):6-9. doi: 10.1158/0008-5472.CAN-08-3026.
• [8] The p400/Tip60 ratio is critical for colorectal cancer cell proliferation through DNA damage response pathways.Oncogene. 2009 Mar 26;28(12):1506-17. doi: 10.1038/onc.2008.499. Epub 2009 Jan 26.
• [9] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] 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.
• [12] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [13] 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.
• [14] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [15] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [16] 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.
• [17] 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.
• [18] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [19] 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.
• [20] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [21] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.