Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTN0W2SW)

• DOT Name: Histone acetyltransferase KAT2A (KAT2A)
• Synonyms: EC 2.3.1.48; General control of amino acid synthesis protein 5-like 2; Histone acetyltransferase GCN5; hGCN5; Histone glutaryltransferase KAT2A; EC 2.3.1.-; Histone succinyltransferase KAT2A; EC 2.3.1.-; Lysine acetyltransferase 2A; STAF97
• Gene Name: KAT2A
• Related Disease:
  Gastric cancer
  Matthew-Wood syndrome
  Metabolic disorder
  Pancreatic ductal carcinoma
  Rheumatoid arthritis
  Stomach cancer
  Acute lymphocytic leukaemia
  Acute monocytic leukemia
  Advanced cancer
  Atrichia with papular lesions
  Autoimmune disease
  Autosomal dominant cerebellar ataxia type II
  B-cell acute lymphoblastic leukaemia
  Breast cancer
  Breast carcinoma
  Burkitt lymphoma
  Cervical cancer
  Cervical carcinoma
  Crohn disease
  Epithelial ovarian cancer
  Glioma
  Hereditary nonpolyposis colon cancer
  Inflammatory bowel disease
  Invasive aspergillosis
  Kennedy disease
  Lynch syndrome
  Non-small-cell lung cancer
  Ovarian cancer
  Ovarian neoplasm
  Promyelocytic leukaemia
  Prostate cancer
  Prostate carcinoma
  Transitional cell carcinoma
  Urothelial carcinoma
  Benign neoplasm
  Central nervous system neoplasm
  Coronary heart disease
  Metastatic malignant neoplasm
  Acute myelogenous leukaemia
  Hepatocellular carcinoma
  leukaemia
  Leukemia
  Nasopharyngeal carcinoma
  Osteoporosis
  Subarachnoid hemorrhage
• UniProt ID: KAT2A_HUMAN
• PDB ID: 1F68; 1Z4R; 3D7C; 5H84; 5H86; 5MLJ; 5TRL; 5TRM; 6J3P; 8H65; 8H66; 8H6C; 8H6D
• EC Number: 2.3.1.-; 2.3.1.48
• Pfam ID: PF00583 ; PF00439 ; PF06466
• Sequence:
  MAEPSQAPTPAPAAQPRPLQSPAPAPTPTPAPSPASAPIPTPTPAPAPAPAAAPAGSTGT
  GGPGVGSGGAGSGGDPARPGLSQQQRASQRKAQVRGLPRAKKLEKLGVFSACKANETCKC
  NGWKNPKPPTAPRMDLQQPAANLSELCRSCEHPLADHVSHLENVSEDEINRLLGMVVDVE
  NLFMSVHKEEDTDTKQVYFYLFKLLRKCILQMTRPVVEGSLGSPPFEKPNIEQGVLNFVQ
  YKFSHLAPRERQTMFELSKMFLLCLNYWKLETPAQFRQRSQAEDVATYKVNYTRWLCYCH
  VPQSCDSLPRYETTHVFGRSLLRSIFTVTRRQLLEKFRVEKDKLVPEKRTLILTHFPKFL
  SMLEEEIYGANSPIWESGFTMPPSEGTQLVPRPASVSAAVVPSTPIFSPSMGGGSNSSLS
  LDSAGAEPMPGEKRTLPENLTLEDAKRLRVMGDIPMELVNEVMLTITDPAAMLGPETSLL
  SANAARDETARLEERRGIIEFHVIGNSLTPKANRRVLLWLVGLQNVFSHQLPRMPKEYIA
  RLVFDPKHKTLALIKDGRVIGGICFRMFPTQGFTEIVFCAVTSNEQVKGYGTHLMNHLKE
  YHIKHNILYFLTYADEYAIGYFKKQGFSKDIKVPKSRYLGYIKDYEGATLMECELNPRIP
  YTELSHIIKKQKEIIKKLIERKQAQIRKVYPGLSCFKEGVRQIPVESVPGIRETGWKPLG
  KEKGKELKDPDQLYTTLKNLLAQIKSHPSAWPFMEPVKKSEAPDYYEVIRFPIDLKTMTE
  RLRSRYYVTRKLFVADLQRVIANCREYNPPDSEYCRCASALEKFFYFKLKEGGLIDK
• Function: Protein lysine acyltransferase that can act as a acetyltransferase, glutaryltransferase, succinyltransferase or malonyltransferase, depending on the context. Acts as a histone lysine succinyltransferase: catalyzes succinylation of histone H3 on 'Lys-79' (H3K79succ), with a maximum frequency around the transcription start sites of genes. Succinylation of histones gives a specific tag for epigenetic transcription activation. Association with the 2-oxoglutarate dehydrogenase complex, which provides succinyl-CoA, is required for histone succinylation. In different complexes, functions either as an acetyltransferase (HAT) or as a succinyltransferase: in the SAGA and ATAC complexes, acts as a histone acetyltransferase. Has significant histone acetyltransferase activity with core histones, but not with nucleosome core particles. Has a a strong preference for acetylation of H3 at 'Lys-9' (H3K9ac). Acetylation of histones gives a specific tag for epigenetic transcription activation. Recruited by the XPC complex at promoters, where it specifically mediates acetylation of histone variant H2A.Z.1/H2A.Z, thereby promoting expression of target genes. Involved in long-term memory consolidation and synaptic plasticity: acts by promoting expression of a hippocampal gene expression network linked to neuroactive receptor signaling. Acts as a positive regulator of T-cell activation: upon TCR stimulation, recruited to the IL2 promoter following interaction with NFATC2 and catalyzes acetylation of histone H3 at 'Lys-9' (H3K9ac), leading to promote IL2 expression. Required for growth and differentiation of craniofacial cartilage and bone by regulating acetylation of histone H3 at 'Lys-9' (H3K9ac). Regulates embryonic stem cell (ESC) pluripotency and differentiation. Also acetylates non-histone proteins, such as CEBPB, PPARGC1A, PLK4 and TBX5. 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. Acts as a negative regulator of gluconeogenesis by mediating acetylation and subsequent inactivation of PPARGC1A. Also acts as a histone glutaryltransferase: catalyzes glutarylation of histone H4 on 'Lys-91' (H4K91glu), a mark that destabilizes nucleosomes by promoting dissociation of the H2A-H2B dimers from nucleosomes ; (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: Expressed in all tissues tested.
• 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:
  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)
  Ub-specific processing proteases (R-HSA-5689880)
  RNA Polymerase I Transcription Initiation (R-HSA-73762)
  RUNX3 regulates NOTCH signaling (R-HSA-8941856)
  NOTCH3 Intracellular Domain Regulates Transcription (R-HSA-9013508)
  NOTCH4 Intracellular Domain Regulates Transcription (R-HSA-9013695)
  Cardiogenesis (R-HSA-9733709)
  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

45 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Gastric cancer	DISXGOUK	Definitive	Altered Expression	[1]
Matthew-Wood syndrome	DISA7HR7	Definitive	Altered Expression	[2]
Metabolic disorder	DIS71G5H	Definitive	Altered Expression	[3]
Pancreatic ductal carcinoma	DIS26F9Q	Definitive	Altered Expression	[2]
Rheumatoid arthritis	DISTSB4J	Definitive	Biomarker	[4]
Stomach cancer	DISKIJSX	Definitive	Altered Expression	[1]
Acute lymphocytic leukaemia	DISPX75S	Strong	Biomarker	[5]
Acute monocytic leukemia	DIS28NEL	Strong	Biomarker	[6]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[7]
Atrichia with papular lesions	DIS80CUB	Strong	Biomarker	[6]
Autoimmune disease	DISORMTM	Strong	Genetic Variation	[8]
Autosomal dominant cerebellar ataxia type II	DIS0PM39	Strong	Altered Expression	[9]
B-cell acute lymphoblastic leukaemia	DISKLOKC	Strong	Biomarker	[5]
Breast cancer	DIS7DPX1	Strong	Biomarker	[10]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[10]
Burkitt lymphoma	DIS9D5XU	Strong	Altered Expression	[11]
Cervical cancer	DISFSHPF	Strong	Biomarker	[12]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[12]
Crohn disease	DIS2C5Q8	Strong	Genetic Variation	[13]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[14]
Glioma	DIS5RPEH	Strong	Biomarker	[15]
Hereditary nonpolyposis colon cancer	DISPA49R	Strong	Biomarker	[16]
Inflammatory bowel disease	DISGN23E	Strong	Genetic Variation	[13]
Invasive aspergillosis	DISAI029	Strong	Biomarker	[17]
Kennedy disease	DISXZVM1	Strong	Biomarker	[14]
Lynch syndrome	DIS3IW5F	Strong	Biomarker	[16]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[18]
Ovarian cancer	DISZJHAP	Strong	Altered Expression	[14]
Ovarian neoplasm	DISEAFTY	Strong	Altered Expression	[14]
Promyelocytic leukaemia	DISYGG13	Strong	Biomarker	[6]
Prostate cancer	DISF190Y	Strong	Biomarker	[19]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[19]
Transitional cell carcinoma	DISWVVDR	Strong	Genetic Variation	[20]
Urothelial carcinoma	DISRTNTN	Strong	Genetic Variation	[20]
Benign neoplasm	DISDUXAD	moderate	Biomarker	[21]
Central nervous system neoplasm	DISFC18W	moderate	Altered Expression	[21]
Coronary heart disease	DIS5OIP1	moderate	Genetic Variation	[22]
Metastatic malignant neoplasm	DIS86UK6	moderate	Genetic Variation	[23]
Acute myelogenous leukaemia	DISCSPTN	Limited	Biomarker	[6]
Hepatocellular carcinoma	DIS0J828	Limited	Biomarker	[24]
leukaemia	DISS7D1V	Limited	Altered Expression	[6]
Leukemia	DISNAKFL	Limited	Altered Expression	[6]
Nasopharyngeal carcinoma	DISAOTQ0	Limited	Altered Expression	[25]
Osteoporosis	DISF2JE0	Limited	Altered Expression	[26]
Subarachnoid hemorrhage	DISI7I8Y	Limited	Altered Expression	[27]

1 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 acetyltransferase KAT2A (KAT2A).	[28]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Histone acetyltransferase KAT2A (KAT2A).	[29]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Histone acetyltransferase KAT2A (KAT2A).	[30]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Histone acetyltransferase KAT2A (KAT2A).	[31]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide affects the expression of Histone acetyltransferase KAT2A (KAT2A).	[32]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Histone acetyltransferase KAT2A (KAT2A).	[33]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Histone acetyltransferase KAT2A (KAT2A).	[33]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Histone acetyltransferase KAT2A (KAT2A).	[34]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Histone acetyltransferase KAT2A (KAT2A).	[35]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Histone acetyltransferase KAT2A (KAT2A).	[36]

References

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• [15] GCN5 Potentiates Glioma Proliferation and Invasion via STAT3 and AKT Signaling Pathways.Int J Mol Sci. 2015 Sep 10;16(9):21897-910. doi: 10.3390/ijms160921897.
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• [17] The histone acetyltransferase GcnE regulates conidiation and biofilm formation in Aspergillus fumigatus.Med Mycol. 2020 Feb 1;58(2):248-259. doi: 10.1093/mmy/myz043.
• [18] Repression of GCN5 expression or activity attenuates c-MYC expression in non-small cell lung cancer.Am J Cancer Res. 2019 Aug 1;9(8):1830-1845. eCollection 2019.
• [19] GCN5 inhibition prevents IL-6-induced prostate cancer metastases through PI3K/PTEN/Akt signaling by inactivating Egr-1.Biosci Rep. 2018 Nov 30;38(6):BSR20180816. doi: 10.1042/BSR20180816. Print 2018 Dec 21.
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• [21] Expression of PCAF, p300 and Gcn5 and more highly acetylated histone H4 in pediatric tumors.J Exp Clin Cancer Res. 2007 Jun;26(2):269-76.
• [22] Identification of 64 Novel Genetic Loci Provides an Expanded View on the Genetic Architecture of Coronary Artery Disease.Circ Res. 2018 Feb 2;122(3):433-443. doi: 10.1161/CIRCRESAHA.117.312086. Epub 2017 Dec 6.
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• [30] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [31] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [32] E2F1-mediated FOS induction in arsenic trioxide-induced cellular transformation: effects of global H3K9 hypoacetylation and promoter-specific hyperacetylation in vitro. Environ Health Perspect. 2015 May;123(5):484-92. doi: 10.1289/ehp.1408302. Epub 2015 Jan 9.
• [33] Time series analysis of oxidative stress response patterns in HepG2: a toxicogenomics approach. Toxicology. 2013 Apr 5;306:24-34.
• [34] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [35] BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell. 2011 Sep 16;146(6):904-17.
• [36] 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.