Details of Drug Off-Target (DOT)

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

• DOT Name: Histone acetyltransferase KAT2B (KAT2B)
• Synonyms: EC 2.3.1.48; Histone acetyltransferase PCAF; Histone acetylase PCAF; Lysine acetyltransferase 2B; P300/CBP-associated factor; P/CAF; Spermidine acetyltransferase KAT2B; EC 2.3.1.57
• Gene Name: KAT2B
• UniProt ID: KAT2B_HUMAN
• PDB ID: 1CM0; 1JM4; 1N72; 1WUG; 1WUM; 1ZS5; 2RNW; 2RNX; 3GG3; 4NSQ; 5FDZ; 5FE0; 5FE1; 5FE2; 5FE3; 5FE4; 5FE5; 5FE6; 5FE7; 5FE8; 5FE9; 5LVQ; 5LVR; 5MKX; 6J3O
• EC Number: 2.3.1.48; 2.3.1.57
• Pfam ID: PF00583 ; PF00439 ; PF06466
• Sequence:
  MSEAGGAGPGGCGAGAGAGAGPGALPPQPAALPPAPPQGSPCAAAAGGSGACGPATAVAA
  AGTAEGPGGGGSARIAVKKAQLRSAPRAKKLEKLGVYSACKAEESCKCNGWKNPNPSPTP
  PRADLQQIIVSLTESCRSCSHALAAHVSHLENVSEEEMNRLLGIVLDVEYLFTCVHKEED
  ADTKQVYFYLFKLLRKSILQRGKPVVEGSLEKKPPFEKPSIEQGVNNFVQYKFSHLPAKE
  RQTIVELAKMFLNRINYWHLEAPSQRRLRSPNDDISGYKENYTRWLCYCNVPQFCDSLPR
  YETTQVFGRTLLRSVFTVMRRQLLEQARQEKDKLPLEKRTLILTHFPKFLSMLEEEVYSQ
  NSPIWDQDFLSASSRTSQLGIQTVINPPPVAGTISYNSTSSSLEQPNAGSSSPACKASSG
  LEANPGEKRKMTDSHVLEEAKKPRVMGDIPMELINEVMSTITDPAAMLGPETNFLSAHSA
  RDEAARLEERRGVIEFHVVGNSLNQKPNKKILMWLVGLQNVFSHQLPRMPKEYITRLVFD
  PKHKTLALIKDGRVIGGICFRMFPSQGFTEIVFCAVTSNEQVKGYGTHLMNHLKEYHIKH
  DILNFLTYADEYAIGYFKKQGFSKEIKIPKTKYVGYIKDYEGATLMGCELNPRIPYTEFS
  VIIKKQKEIIKKLIERKQAQIRKVYPGLSCFKDGVRQIPIESIPGIRETGWKPSGKEKSK
  EPRDPDQLYSTLKSILQQVKSHQSAWPFMEPVKRTEAPGYYEVIRFPMDLKTMSERLKNR
  YYVSKKLFMADLQRVFTNCKEYNPPESEYYKCANILEKFFFSKIKEAGLIDK
• Function: Functions as a histone acetyltransferase (HAT) to promote transcriptional activation. Has significant histone acetyltransferase activity with core histones (H3 and H4), and also with nucleosome core particles. Has a a strong preference for acetylation of H3 at 'Lys-9' (H3K9ac). Also acetylates non-histone proteins, such as ACLY, MAPRE1/EB1, PLK4, RRP9/U3-55K and TBX5. Inhibits cell-cycle progression and counteracts the mitogenic activity of the adenoviral oncoprotein E1A. Acts as a circadian transcriptional coactivator which enhances the activity of the circadian transcriptional activators: NPAS2-BMAL1 and CLOCK-BMAL1 heterodimers. Involved in heart and limb development by mediating acetylation of TBX5, acetylation regulating nucleocytoplasmic shuttling of TBX5. Acts as a negative regulator of centrosome amplification by mediating acetylation of PLK4. Acetylates RRP9/U3-55K, a core subunit of the U3 snoRNP complex, impairing pre-rRNA processing. Acetylates MAPRE1/EB1, promoting dynamic kinetochore-microtubule interactions in early mitosis. Also acetylates spermidine ; (Microbial infection) In case of HIV-1 infection, it is recruited by the viral protein Tat. Regulates Tat's transactivating activity and may help inducing chromatin remodeling of proviral genes.
• Tissue Specificity: Ubiquitously expressed but most abundant in heart and skeletal muscle. Also expressed in the skin, in keratinocytes (at protein level) .
• KEGG Pathway:
  Viral life cycle - HIV-1 (hsa03250)
  Notch sig.ling pathway (hsa04330)
  Thyroid hormone sig.ling pathway (hsa04919)
  Human T-cell leukemia virus 1 infection (hsa05166)
  Viral carcinogenesis (hsa05203)
• Reactome Pathway:
  YAP1- and WWTR1 (TAZ)-stimulated gene expression (R-HSA-2032785)
  Regulation of gene expression in late stage (branching morphogenesis) pancreatic bud precursor cells (R-HSA-210744)
  NOTCH1 Intracellular Domain Regulates Transcription (R-HSA-2122947)
  Constitutive Signaling by NOTCH1 PEST Domain Mutants (R-HSA-2644606)
  Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants (R-HSA-2894862)
  HATs acetylate histones (R-HSA-3214847)
  Notch-HLH transcription pathway (R-HSA-350054)
  B-WICH complex positively regulates rRNA expression (R-HSA-5250924)
  Physiological factors (R-HSA-5578768)
  Metalloprotease DUBs (R-HSA-5689901)
  RNA Polymerase I Transcription Initiation (R-HSA-73762)
  RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function (R-HSA-8936459)
  RUNX3 regulates NOTCH signaling (R-HSA-8941856)
  NOTCH3 Intracellular Domain Regulates Transcription (R-HSA-9013508)
  NOTCH4 Intracellular Domain Regulates Transcription (R-HSA-9013695)
  Estrogen-dependent gene expression (R-HSA-9018519)
  Regulation of FOXO transcriptional activity by acetylation (R-HSA-9617629)
  Formation of WDR5-containing histone-modifying complexes (R-HSA-9772755)
  Formation of paraxial mesoderm (R-HSA-9793380)
  Pre-NOTCH Transcription and Translation (R-HSA-1912408)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Histone acetyltransferase KAT2B (KAT2B).	[1]

27 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 acetyltransferase KAT2B (KAT2B).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Histone acetyltransferase KAT2B (KAT2B).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Histone acetyltransferase KAT2B (KAT2B).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Histone acetyltransferase KAT2B (KAT2B).	[5]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Histone acetyltransferase KAT2B (KAT2B).	[6]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Histone acetyltransferase KAT2B (KAT2B).	[7]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Histone acetyltransferase KAT2B (KAT2B).	[8]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Histone acetyltransferase KAT2B (KAT2B).	[9]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Histone acetyltransferase KAT2B (KAT2B).	[10]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Histone acetyltransferase KAT2B (KAT2B).	[11]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Histone acetyltransferase KAT2B (KAT2B).	[12]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Histone acetyltransferase KAT2B (KAT2B).	[13]
Irinotecan	DMP6SC2	Approved	Irinotecan increases the expression of Histone acetyltransferase KAT2B (KAT2B).	[14]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol decreases the expression of Histone acetyltransferase KAT2B (KAT2B).	[15]
Enzalutamide	DMGL19D	Approved	Enzalutamide affects the expression of Histone acetyltransferase KAT2B (KAT2B).	[16]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Histone acetyltransferase KAT2B (KAT2B).	[17]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Histone acetyltransferase KAT2B (KAT2B).	[11]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Histone acetyltransferase KAT2B (KAT2B).	[18]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Histone acetyltransferase KAT2B (KAT2B).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Histone acetyltransferase KAT2B (KAT2B).	[20]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Histone acetyltransferase KAT2B (KAT2B).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Histone acetyltransferase KAT2B (KAT2B).	[22]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Histone acetyltransferase KAT2B (KAT2B).	[23]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Histone acetyltransferase KAT2B (KAT2B).	[24]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Histone acetyltransferase KAT2B (KAT2B).	[25]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Histone acetyltransferase KAT2B (KAT2B).	[26]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate decreases the expression of Histone acetyltransferase KAT2B (KAT2B).	[27]

References

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• [11] 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.
• [12] Dexamethasone controls aryl hydrocarbon receptor (AhR)-mediated CYP1A1 and CYP1A2 expression and activity in primary cultures of human hepatocytes. Chem Biol Interact. 2009 May 15;179(2-3):288-96.
• [13] Synergistic antiproliferative effect of arsenic trioxide combined with bortezomib in HL60 cell line and primary blasts from patients affected by myeloproliferative disorders. Cancer Genet Cytogenet. 2010 Jun;199(2):110-20. doi: 10.1016/j.cancergencyto.2010.02.010.
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• [16] NOTCH signaling is activated in and contributes to resistance in enzalutamide-resistant prostate cancer cells. J Biol Chem. 2019 May 24;294(21):8543-8554. doi: 10.1074/jbc.RA118.006983. Epub 2019 Apr 2.
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• [18] Resveratrol-induced gene expression profiles in human prostate cancer cells. Cancer Epidemiol Biomarkers Prev. 2005 Mar;14(3):596-604. doi: 10.1158/1055-9965.EPI-04-0398.
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• [20] Influence of cell cycle on responses of MCF-7 cells to benzo[a]pyrene. BMC Genomics. 2011 Jun 29;12:333.
• [21] BET bromodomain inhibition as a novel strategy for reactivation of HIV-1. J Leukoc Biol. 2012 Dec;92(6):1147-54. doi: 10.1189/jlb.0312165. Epub 2012 Jul 16.
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• [23] Epigenetic changes and disturbed neural development in a human embryonic stem cell-based model relating to the fetal valproate syndrome. Hum Mol Genet. 2012 Sep 15;21(18):4104-14. doi: 10.1093/hmg/dds239. Epub 2012 Jun 20.
• [24] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [25] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [26] Sulforaphane-induced apoptosis in human leukemia HL-60 cells through extrinsic and intrinsic signal pathways and altering associated genes expression assayed by cDNA microarray. Environ Toxicol. 2017 Jan;32(1):311-328.
• [27] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.