Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT307KEN)

• DOT Name: Histone acetyltransferase type B catalytic subunit (HAT1)
• Synonyms: EC 2.3.1.48; Histone acetyltransferase 1
• Gene Name: HAT1
• Related Disease:
  Advanced cancer
  Arteriosclerosis
  Atherosclerosis
  Breast cancer
  Breast carcinoma
  Carcinoma of esophagus
  Crohn disease
  Depression
  Esophageal squamous cell carcinoma
  Hyperlipidemia
  Immunodeficiency
  Inflammatory bowel disease
  Major depressive disorder
  Matthew-Wood syndrome
  Neoplasm
  Pancreatic cancer
  Psoriasis
  Schizophrenia
  Ulcerative colitis
  Hepatocellular carcinoma
  Bone osteosarcoma
  Lung cancer
  Lung carcinoma
  Malignant tumor of nasopharynx
  Nasopharyngeal carcinoma
  Osteosarcoma
• UniProt ID: HAT1_HUMAN
• PDB ID: 2P0W; 6VO5
• EC Number: 2.3.1.48
• Pfam ID: PF21183 ; PF10394
• Sequence:
  MAGFGAMEKFLVEYKSAVEKKLAEYKCNTNTAIELKLVRFPEDLENDIRTFFPEYTHQLF
  GDDETAFGYKGLKILLYYIAGSLSTMFRVEYASKVDENFDCVEADDVEGKIRQIIPPGFC
  TNTNDFLSLLEKEVDFKPFGTLLHTYSVLSPTGGENFTFQIYKADMTCRGFREYHERLQT
  FLMWFIETASFIDVDDERWHYFLVFEKYNKDGATLFATVGYMTVYNYYVYPDKTRPRVSQ
  MLILTPFQGQGHGAQLLETVHRYYTEFPTVLDITAEDPSKSYVKLRDFVLVKLCQDLPCF
  SREKLMQGFNEDMVIEAQQKFKINKQHARRVYEILRLLVTDMSDAEQYRSYRLDIKRRLI
  SPYKKKQRDLAKMRKCLRPEELTNQMNQIEISMQHEQLEESFQELVEDYRRVIERLAQE
• Function: Histone acetyltransferase that plays a role in different biological processes including cell cycle progression, glucose metabolism, histone production or DNA damage repair. Coordinates histone production and acetylation via H4 promoter binding. Acetylates histone H4 at 'Lys-5' (H4K5ac) and 'Lys-12' (H4K12ac) and, to a lesser extent, histone H2A at 'Lys-5' (H2AK5ac). Drives H4 production by chromatin binding to support chromatin replication and acetylation. Since transcription of H4 genes is tightly coupled to S-phase, plays an important role in S-phase entry and progression. Promotes homologous recombination in DNA repair by facilitating histone turnover and incorporation of acetylated H3.3 at sites of double-strand breaks. In addition, acetylates other substrates such as chromatin-related proteins. Acetylates also RSAD2 which mediates the interaction of ubiquitin ligase UBE4A with RSAD2 leading to RSAD2 ubiquitination and subsequent degradation ; (Microbial infection) Contributes to hepatitis B virus (HBV) replication by acetylating histone H4 at the sites of 'Lys-5' and 'Lys-12' on the covalently closed circular DNA (cccDNA) minichromosome leading to its accumulation within the host cell.
• KEGG Pathway:
  Neutrophil extracellular trap formation (hsa04613)
  Alcoholism (hsa05034)
• Reactome Pathway: HATs acetylate histones (R-HSA-3214847)

Molecular Interaction Atlas (MIA) of This DOT

26 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[2]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[3]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[3]
Carcinoma of esophagus	DISS6G4D	Strong	Biomarker	[4]
Crohn disease	DIS2C5Q8	Strong	Altered Expression	[5]
Depression	DIS3XJ69	Strong	Genetic Variation	[6]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[4]
Hyperlipidemia	DIS61J3S	Strong	Biomarker	[7]
Immunodeficiency	DIS093I0	Strong	Biomarker	[8]
Inflammatory bowel disease	DISGN23E	Strong	Altered Expression	[5]
Major depressive disorder	DIS4CL3X	Strong	Biomarker	[9]
Matthew-Wood syndrome	DISA7HR7	Strong	Altered Expression	[1]
Neoplasm	DISZKGEW	Strong	Biomarker	[1]
Pancreatic cancer	DISJC981	Strong	Biomarker	[1]
Psoriasis	DIS59VMN	Strong	Biomarker	[10]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[11]
Ulcerative colitis	DIS8K27O	Strong	Altered Expression	[5]
Hepatocellular carcinoma	DIS0J828	moderate	Biomarker	[12]
Bone osteosarcoma	DIST1004	Limited	Altered Expression	[13]
Lung cancer	DISCM4YA	Limited	Altered Expression	[14]
Lung carcinoma	DISTR26C	Limited	Altered Expression	[14]
Malignant tumor of nasopharynx	DISTGIGF	Limited	Altered Expression	[15]
Nasopharyngeal carcinoma	DISAOTQ0	Limited	Altered Expression	[15]
Osteosarcoma	DISLQ7E2	Limited	Altered Expression	[13]

18 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 acetyltransferase type B catalytic subunit (HAT1).	[16]
Ciclosporin	DMAZJFX	Approved	Ciclosporin affects the expression of Histone acetyltransferase type B catalytic subunit (HAT1).	[17]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Histone acetyltransferase type B catalytic subunit (HAT1).	[18]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Histone acetyltransferase type B catalytic subunit (HAT1).	[19]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Histone acetyltransferase type B catalytic subunit (HAT1).	[20]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Histone acetyltransferase type B catalytic subunit (HAT1).	[21]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Histone acetyltransferase type B catalytic subunit (HAT1).	[22]
Quercetin	DM3NC4M	Approved	Quercetin increases the activity of Histone acetyltransferase type B catalytic subunit (HAT1).	[24]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Histone acetyltransferase type B catalytic subunit (HAT1).	[25]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Histone acetyltransferase type B catalytic subunit (HAT1).	[26]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Histone acetyltransferase type B catalytic subunit (HAT1).	[27]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Histone acetyltransferase type B catalytic subunit (HAT1).	[28]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Histone acetyltransferase type B catalytic subunit (HAT1).	[29]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Histone acetyltransferase type B catalytic subunit (HAT1).	[30]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Histone acetyltransferase type B catalytic subunit (HAT1).	[28]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Histone acetyltransferase type B catalytic subunit (HAT1).	[31]
Berberine	DMC5Q8X	Phase 4	Berberine increases the expression of Histone acetyltransferase type B catalytic subunit (HAT1).	[32]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Histone acetyltransferase type B catalytic subunit (HAT1).	[34]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of Histone acetyltransferase type B catalytic subunit (HAT1).	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Histone acetyltransferase type B catalytic subunit (HAT1).	[33]

References

• [1] Overexpressed histone acetyltransferase 1 regulates cancer immunity by increasing programmed death-ligand 1 expression in pancreatic cancer.J Exp Clin Cancer Res. 2019 Feb 1;38(1):47. doi: 10.1186/s13046-019-1044-z.
• [2] Histone Acetyltransferase-Dependent Pathways Mediate Upregulation of NADPH Oxidase 5 in Human Macrophages under Inflammatory Conditions: A Potential Mechanism of Reactive Oxygen Species Overproduction in Atherosclerosis.Oxid Med Cell Longev. 2019 Sep 2;2019:3201062. doi: 10.1155/2019/3201062. eCollection 2019.
• [3] Epigenetic modifications, chromatin distribution and TP53 transcription in a model of breast cancer progression.J Cell Biochem. 2015 Apr;116(4):533-41. doi: 10.1002/jcb.25003.
• [4] RNAi screening identifies HAT1 as a potential drug target in esophageal squamous cell carcinoma.Int J Clin Exp Pathol. 2014 Jun 15;7(7):3898-907. eCollection 2014.
• [5] Increased expression of kynurenine aminotransferases mRNA in lymphocytes of patients with inflammatory bowel disease.Therap Adv Gastroenterol. 2019 Oct 19;12:1756284819881304. doi: 10.1177/1756284819881304. eCollection 2019.
• [6] Variation of genes encoding KAT1, AADAT and IDO1 as a potential risk of depression development.Eur Psychiatry. 2018 Aug;52:95-103. doi: 10.1016/j.eurpsy.2018.05.001. Epub 2018 May 25.
• [7] Swertiamarin decreases lipid accumulation dependent on 3-ketoacyl-coA thiolase.Biomed Pharmacother. 2019 Apr;112:108668. doi: 10.1016/j.biopha.2019.108668. Epub 2019 Feb 20.
• [8] Epigenetic alterations are associated with monocyte immune dysfunctions in HIV-1 infection.Sci Rep. 2018 Apr 3;8(1):5505. doi: 10.1038/s41598-018-23841-1.
• [9] Tryptophan depletion in depressed patients occurs independent of kynurenine pathway activation.Brain Behav Immun. 2012 Aug;26(6):979-87. doi: 10.1016/j.bbi.2012.05.010. Epub 2012 Jun 6.
• [10] Efficacy and safety of HAT1 compared with calcipotriol in the treatment of patients with mild to moderate chronic plaque psoriasis: results from an open-label randomized comparative pilot clinical study.Clin Exp Dermatol. 2020 Apr;45(3):318-322. doi: 10.1111/ced.14074. Epub 2019 Sep 26.
• [11] Pleiotropic Meta-Analysis of Cognition, Education, and Schizophrenia Differentiates Roles of Early Neurodevelopmental and Adult Synaptic Pathways.Am J Hum Genet. 2019 Aug 1;105(2):334-350. doi: 10.1016/j.ajhg.2019.06.012.
• [12] Histone Acetyltransferase 1 Promotes Cell Proliferation and Induces Cisplatin Resistance in Hepatocellular Carcinoma.Oncol Res. 2017 Jul 5;25(6):939-946. doi: 10.3727/096504016X14809827856524. Epub 2016 Dec 8.
• [13] Ras-ERK1/2 signalling promotes the development of osteosarcoma through regulation of H4K12ac through HAT1.Artif Cells Nanomed Biotechnol. 2019 Dec;47(1):1207-1215. doi: 10.1080/21691401.2019.1593857.
• [14] HAT1 induces lung cancer cell apoptosis via up regulating Fas.Oncotarget. 2017 Sep 23;8(52):89970-89977. doi: 10.18632/oncotarget.21205. eCollection 2017 Oct 27.
• [15] Histone acetyltransferase 1 up regulates Bcl2L12 expression in nasopharyngeal cancer cells.Arch Biochem Biophys. 2018 May 15;646:72-79. doi: 10.1016/j.abb.2018.03.040. Epub 2018 Apr 3.
• [16] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [17] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [18] Retinoic acid-induced downmodulation of telomerase activity in human cancer cells. Exp Mol Pathol. 2005 Oct;79(2):108-17.
• [19] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [20] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [21] Effects of chronic exposure to arsenic and estrogen on epigenetic regulatory genes expression and epigenetic code in human prostate epithelial cells. PLoS One. 2012;7(8):e43880. doi: 10.1371/journal.pone.0043880. Epub 2012 Aug 27.
• [22] 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.
• [23] Epigenetic changes in individuals with arsenicosis. Chem Res Toxicol. 2011 Feb 18;24(2):165-7. doi: 10.1021/tx1004419. Epub 2011 Feb 4.
• [24] Quercetin induces FasL-related apoptosis, in part, through promotion of histone H3 acetylation in human leukemia HL-60 cells. Oncol Rep. 2011 Feb;25(2):583-91. doi: 10.3892/or.2010.1097. Epub 2010 Dec 10.
• [25] Proteomics-based identification of differentially abundant proteins from human keratinocytes exposed to arsenic trioxide. J Proteomics Bioinform. 2014 Jul;7(7):166-178.
• [26] Oxidative stress-induced epigenetic changes associated with malignant transformation of human kidney epithelial cells. Oncotarget. 2017 Feb 14;8(7):11127-11143. doi: 10.18632/oncotarget.12091.
• [27] 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.
• [28] Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNF-mediated hepatotoxicity. Toxicol Sci. 2014 Jul;140(1):144-59. doi: 10.1093/toxsci/kfu072. Epub 2014 Apr 20.
• [29] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [30] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [31] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [32] Berberine acts as a putative epigenetic modulator by affecting the histone code. Toxicol In Vitro. 2016 Oct;36:10-17. doi: 10.1016/j.tiv.2016.06.004. Epub 2016 Jun 13.
• [33] 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.
• [34] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.