Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTUN98IC)

• DOT Name: Histone acetyltransferase KAT7 (KAT7)
• Synonyms: EC 2.3.1.48; Histone acetyltransferase binding to ORC1; Lysine acetyltransferase 7; MOZ, YBF2/SAS3, SAS2 and TIP60 protein 2; MYST-2
• Gene Name: KAT7
• Related Disease:
  Acute monocytic leukemia
  Acute myelogenous leukaemia
  Advanced cancer
  Androgen insensitivity syndrome
  Bladder cancer
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Carcinoma
  Chronic myelomonocytic leukaemia
  Chronic myelomonocytic leukemia
  Colorectal carcinoma
  Epithelial ovarian cancer
  Hepatocellular carcinoma
  Leukemia
  Ovarian cancer
  Ovarian neoplasm
  Urinary bladder cancer
  Urinary bladder neoplasm
  Xeroderma pigmentosum
  Rheumatoid arthritis
  Gastric cancer
  Stomach cancer
• UniProt ID: KAT7_HUMAN
• PDB ID: 5GK9; 6MAJ; 6MAK; 7D0O; 7D0P; 7D0Q; 7D0R; 7D0S
• EC Number: 2.3.1.48
• Pfam ID: PF01853 ; PF01530 ; PF17772
• Sequence:
  MPRRKRNAGSSSDGTEDSDFSTDLEHTDSSESDGTSRRSARVTRSSARLSQSSQDSSPVR
  NLQSFGTEEPAYSTRRVTRSQQQPTPVTPKKYPLRQTRSSGSETEQVVDFSDRETKNTAD
  HDESPPRTPTGNAPSSESDIDISSPNVSHDESIAKDMSLKDSGSDLSHRPKRRRFHESYN
  FNMKCPTPGCNSLGHLTGKHERHFSISGCPLYHNLSADECKVRAQSRDKQIEERMLSHRQ
  DDNNRHATRHQAPTERQLRYKEKVAELRKKRNSGLSKEQKEKYMEHRQTYGNTREPLLEN
  LTSEYDLDLFRRAQARASEDLEKLRLQGQITEGSNMIKTIAFGRYELDTWYHSPYPEEYA
  RLGRLYMCEFCLKYMKSQTILRRHMAKCVWKHPPGDEIYRKGSISVFEVDGKKNKIYCQN
  LCLLAKLFLDHKTLYYDVEPFLFYVMTEADNTGCHLIGYFSKEKNSFLNYNVSCILTMPQ
  YMRQGYGKMLIDFSYLLSKVEEKVGSPERPLSDLGLISYRSYWKEVLLRYLHNFQGKEIS
  IKEISQETAVNPVDIVSTLQALQMLKYWKGKHLVLKRQDLIDEWIAKEAKRSNSNKTMDP
  SCLKWTPPKGT
• Function: Catalytic subunit of histone acetyltransferase HBO1 complexes, which specifically mediate acetylation of histone H3 at 'Lys-14' (H3K14ac), thereby regulating various processes, such as gene transcription, protein ubiquitination, immune regulation, stem cell pluripotent and self-renewal maintenance and embryonic development. Some complexes also catalyze acetylation of histone H4 at 'Lys-5', 'Lys-8' and 'Lys-12' (H4K5ac, H4K8ac and H4K12ac, respectively), regulating DNA replication initiation, regulating DNA replication initiation. Specificity of the HBO1 complexes is determined by the scaffold subunit: complexes containing BRPF scaffold (BRPF1, BRD1/BRPF2 or BRPF3) direct KAT7/HBO1 specificity towards H3K14ac, while complexes containing JADE (JADE1, JADE2 and JADE3) scaffold direct KAT7/HBO1 specificity towards histone H4. H3K14ac promotes transcriptional elongation by facilitating the processivity of RNA polymerase II. Acts as a key regulator of hematopoiesis by forming a complex with BRD1/BRPF2, directing KAT7/HBO1 specificity towards H3K14ac and promoting erythroid differentiation. H3K14ac is also required for T-cell development. KAT7/HBO1-mediated acetylation facilitates two consecutive steps, licensing and activation, in DNA replication initiation: H3K14ac facilitates the activation of replication origins, and histone H4 acetylation (H4K5ac, H4K8ac and H4K12ac) facilitates chromatin loading of MCM complexes, promoting DNA replication licensing. Acts as a positive regulator of centromeric CENPA assembly: recruited to centromeres and mediates histone acetylation, thereby preventing centromere inactivation mediated by SUV39H1, possibly by increasing histone turnover/exchange. Involved in nucleotide excision repair: phosphorylation by ATR in response to ultraviolet irradiation promotes its localization to DNA damage sites, where it mediates histone acetylation to facilitate recruitment of XPC at the damaged DNA sites. Acts as an inhibitor of NF-kappa-B independently of its histone acetyltransferase activity ; Plays a central role in the maintenance of leukemia stem cells in acute myeloid leukemia (AML). Acts by mediating acetylation of histone H3 at 'Lys-14' (H3K14ac), thereby facilitating the processivity of RNA polymerase II to maintain the high expression of key genes, such as HOXA9 and HOXA10 that help to sustain the functional properties of leukemia stem cells.
• Tissue Specificity: Ubiquitously expressed, with highest levels in testis.
• Reactome Pathway: HATs acetylate histones (R-HSA-3214847)

Molecular Interaction Atlas (MIA) of This DOT

23 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute monocytic leukemia	DIS28NEL	Strong	Altered Expression	[1]
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[3]
Androgen insensitivity syndrome	DISUZBBO	Strong	Biomarker	[4]
Bladder cancer	DISUHNM0	Strong	Biomarker	[5]
Breast cancer	DIS7DPX1	Strong	Biomarker	[6]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[6]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[6]
Carcinoma	DISH9F1N	Strong	Altered Expression	[7]
Chronic myelomonocytic leukaemia	DISDN5P7	Strong	Biomarker	[8]
Chronic myelomonocytic leukemia	DISIL8UR	Strong	Altered Expression	[8]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[9]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[10]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[3]
Leukemia	DISNAKFL	Strong	Biomarker	[2]
Ovarian cancer	DISZJHAP	Strong	Altered Expression	[10]
Ovarian neoplasm	DISEAFTY	Strong	Altered Expression	[10]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[5]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[5]
Xeroderma pigmentosum	DISQ9H19	Strong	Biomarker	[11]
Rheumatoid arthritis	DISTSB4J	Disputed	Altered Expression	[12]
Gastric cancer	DISXGOUK	Limited	Biomarker	[13]
Stomach cancer	DISKIJSX	Limited	Biomarker	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Histone acetyltransferase KAT7 (KAT7).	[14]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Histone acetyltransferase KAT7 (KAT7).	[15]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Histone acetyltransferase KAT7 (KAT7).	[16]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Histone acetyltransferase KAT7 (KAT7).	[17]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Histone acetyltransferase KAT7 (KAT7).	[18]
Aspirin	DM672AH	Approved	Aspirin decreases the expression of Histone acetyltransferase KAT7 (KAT7).	[19]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Histone acetyltransferase KAT7 (KAT7).	[18]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Histone acetyltransferase KAT7 (KAT7).	[18]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of Histone acetyltransferase KAT7 (KAT7).	[21]
Phencyclidine	DMQBEYX	Investigative	Phencyclidine increases the expression of Histone acetyltransferase KAT7 (KAT7).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Histone acetyltransferase KAT7 (KAT7).	[20]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Histone acetyltransferase KAT7 (KAT7).	[20]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid increases the phosphorylation of Histone acetyltransferase KAT7 (KAT7).	[22]

References

• [1] MYST2 acetyltransferase expression and Histone H4 Lysine acetylation are suppressed in AML.Exp Hematol. 2015 Sep;43(9):794-802.e4. doi: 10.1016/j.exphem.2015.05.010. Epub 2015 Jun 11.
• [2] HBO1 is required for the maintenance of leukaemia stem cells.Nature. 2020 Jan;577(7789):266-270. doi: 10.1038/s41586-019-1835-6. Epub 2019 Dec 11.
• [3] miR-639 Expression Is Silenced by DNMT3A-Mediated Hypermethylation and Functions as a Tumor Suppressor in Liver Cancer Cells.Mol Ther. 2020 Feb 5;28(2):587-598. doi: 10.1016/j.ymthe.2019.11.021. Epub 2019 Nov 28.
• [4] Expression and characterization of androgen receptor coregulators, SRC-2 and HBO1, during human testis ontogenesis and in androgen signaling deficient patients.Mol Cell Endocrinol. 2013 Aug 15;375(1-2):140-8. doi: 10.1016/j.mce.2013.05.004. Epub 2013 May 24.
• [5] HBO1 promotes cell proliferation in bladder cancer via activation of Wnt/-catenin signaling.Mol Carcinog. 2018 Jan;57(1):12-21. doi: 10.1002/mc.22715. Epub 2017 Sep 2.
• [6] Hbo1 is a cyclin E/CDK2 substrate that enriches breast cancer stem-like cells.Cancer Res. 2013 Sep 1;73(17):5556-68. doi: 10.1158/0008-5472.CAN-13-0013. Epub 2013 Aug 16.
• [7] Histone acetyltransferase Hbo1: catalytic activity, cellular abundance, and links to primary cancers.Gene. 2009 May 1;436(1-2):108-14. doi: 10.1016/j.gene.2009.01.020. Epub 2009 Feb 10.
• [8] NUP98-HBO1-fusion generates phenotypically and genetically relevant chronic myelomonocytic leukemia pathogenesis.Blood Adv. 2019 Apr 9;3(7):1047-1060. doi: 10.1182/bloodadvances.2018025007.
• [9] A novel long non-coding RNA-KAT7 is low expressed in colorectal cancer and acts as a tumor suppressor.Cancer Cell Int. 2019 Feb 26;19:40. doi: 10.1186/s12935-019-0760-y. eCollection 2019.
• [10] HBO1 directs histone H4 specific acetylation, potentiating mechano-transduction pathways and membrane elasticity in ovarian cancer cells.Nanomedicine. 2019 Apr;17:254-265. doi: 10.1016/j.nano.2019.01.017. Epub 2019 Feb 10.
• [11] Phosphorylated HBO1 at UV irradiated sites is essential for nucleotide excision repair.Nat Commun. 2017 Jul 18;8:16102. doi: 10.1038/ncomms16102.
• [12] Upregulated KAT7 in synovial fibroblasts promotes Th17cell differentiation and infiltration in rheumatoid arthritis.Biochem Biophys Res Commun. 2017 Jul 22;489(2):235-241. doi: 10.1016/j.bbrc.2017.05.143. Epub 2017 May 26.
• [13] High-Expression HBO1 Predicts Poor Prognosis in Gastric Cancer.Am J Clin Pathol. 2019 Sep 9;152(4):517-526. doi: 10.1093/ajcp/aqz065.
• [14] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [15] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [16] 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.
• [17] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [18] 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.
• [19] Expression profile analysis of human peripheral blood mononuclear cells in response to aspirin. Arch Immunol Ther Exp (Warsz). 2005 Mar-Apr;53(2):151-8.
• [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] 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.
• [22] Functional lipidomics: Palmitic acid impairs hepatocellular carcinoma development by modulating membrane fluidity and glucose metabolism. Hepatology. 2017 Aug;66(2):432-448. doi: 10.1002/hep.29033. Epub 2017 Jun 16.
• [23] Differential response of Mono Mac 6, BEAS-2B, and Jurkat cells to indoor dust. Environ Health Perspect. 2007 Sep;115(9):1325-32.