Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZ9P12A)

• DOT Name: N-acetyltransferase ESCO1 (ESCO1)
• Synonyms: EC 2.3.1.-; CTF7 homolog 1; Establishment factor-like protein 1; EFO1; EFO1p; hEFO1; Establishment of cohesion 1 homolog 1; ECO1 homolog 1; ESO1 homolog 1
• Gene Name: ESCO1
• Related Disease:
  Advanced cancer
  Amyloidosis
  Bladder cancer
  Dementia
  Diabetic kidney disease
  Esophageal squamous cell carcinoma
  Gastric cancer
  Mesothelioma
  Prostate cancer
  Prostate carcinoma
  Roberts-SC phocomelia syndrome
  Schwannomatosis
  Urinary bladder cancer
  Urinary bladder neoplasm
  Melanoma
  Neuroblastoma
  Neurofibromatosis
  Neurofibromatosis type 1
  Alzheimer disease
  Neoplasm
• UniProt ID: ESCO1_HUMAN
• PDB ID: 4MXE; 5T53
• EC Number: 2.3.1.-
• Pfam ID: PF13880 ; PF13878
• Sequence:
  MMSIQEKSKENSSKVTKKSDDKNSETEIQDSQKNLAKKSGPKETIKSQAKSSSESKINQP
  ELETRMSTRSSKAASNDKATKSINKNTVTVRGYSQESTKKKLSQKKLVHENPKANEQLNR
  RSQRLQQLTEVSRRSLRSREIQGQVQAVKQSLPPTKKEQCSSTQSKSNKTSQKHVKRKVL
  EVKSDSKEDENLVINEVINSPKGKKRKVEHQTACACSSQCTQGSEKCPQKTTRRDETKPV
  PVTSEVKRSKMATSVVPKKNEMKKSVHTQVNTNTTLPKSPQPSVPEQSDNELEQAGKSKR
  GSILQLCEEIAGEIESDNVEVKKESSQMESVKEEKPTEIKLEETSVERQILHQKETNQDV
  QCNRFFPSRKTKPVKCILNGINSSAKKNSNWTKIKLSKFNSVQHNKLDSQVSPKLGLLRT
  SFSPPALEMHHPVTQSTFLGTKLHDRNITCQQEKMKEINSEEVKINDITVEINKTTERAP
  ENCHLANEIKPSDPPLDNQMKHSFDSASNKNFSQCLESKLENSPVENVTAASTLLSQAKI
  DTGENKFPGSAPQQHSILSNQTSKSSDNRETPRNHSLPKCNSHLEITIPKDLKLKEAEKT
  DEKQLIIDAGQKRFGAVSCNVCGMLYTASNPEDETQHLLFHNQFISAVKYVGWKKERILA
  EYPDGRIIMVLPEDPKYALKKVDEIREMVDNDLGFQQAPLMCYSRTKTLLFISNDKKVVG
  CLIAEHIQWGYRVIEEKLPVIRSEEEKVRFERQKAWCCSTLPEPAICGISRIWVFSMMRR
  KKIASRMIECLRSNFIYGSYLSKEEIAFSDPTPDGKLFATQYCGTGQFLVYNFINGQNST
• Function: Acetyltransferase required for the establishment of sister chromatid cohesion. Couples the processes of cohesion and DNA replication to ensure that only sister chromatids become paired together. In contrast to the structural cohesins, the deposition and establishment factors are required only during S phase. Acts by mediating the acetylation of cohesin component SMC3.
• Tissue Specificity: Widely expressed. Expressed in heart, brain, liver, placenta, lung, kidney and pancreas. Highly expressed in muscle.
• KEGG Pathway: Cell cycle (hsa04110)
• Reactome Pathway: Establishment of Sister Chromatid Cohesion (R-HSA-2468052)

Molecular Interaction Atlas (MIA) of This DOT

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Amyloidosis	DISHTAI2	Strong	Biomarker	[2]
Bladder cancer	DISUHNM0	Strong	Biomarker	[3]
Dementia	DISXL1WY	Strong	Biomarker	[4]
Diabetic kidney disease	DISJMWEY	Strong	Biomarker	[5]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[6]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[7]
Mesothelioma	DISKWK9M	Strong	Posttranslational Modification	[1]
Prostate cancer	DISF190Y	Strong	Biomarker	[8]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[8]
Roberts-SC phocomelia syndrome	DIS4JXZ4	Strong	Genetic Variation	[9]
Schwannomatosis	DISDWAM1	Strong	Biomarker	[10]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[3]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[3]
Melanoma	DIS1RRCY	moderate	Biomarker	[11]
Neuroblastoma	DISVZBI4	moderate	Biomarker	[12]
Neurofibromatosis	DIS5N2R6	moderate	Biomarker	[13]
Neurofibromatosis type 1	DIS53JH9	moderate	Biomarker	[13]
Alzheimer disease	DISF8S70	Limited	Biomarker	[14]
Neoplasm	DISZKGEW	Limited	Altered Expression	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of N-acetyltransferase ESCO1 (ESCO1).	[15]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of N-acetyltransferase ESCO1 (ESCO1).	[16]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of N-acetyltransferase ESCO1 (ESCO1).	[17]
Clorgyline	DMCEUJD	Approved	Clorgyline increases the expression of N-acetyltransferase ESCO1 (ESCO1).	[18]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of N-acetyltransferase ESCO1 (ESCO1).	[20]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of N-acetyltransferase ESCO1 (ESCO1).	[22]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of N-acetyltransferase ESCO1 (ESCO1).	[23]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of N-acetyltransferase ESCO1 (ESCO1).	[24]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of N-acetyltransferase ESCO1 (ESCO1).	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of N-acetyltransferase ESCO1 (ESCO1).	[19]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of N-acetyltransferase ESCO1 (ESCO1).	[21]

References

• [1] HDAC1-mSin3a-NCOR1, Dnmt3b-HDAC1-Egr1 and Dnmt1-PCNA-UHRF1-G9a regulate the NY-ESO1 gene expression.Mol Oncol. 2013 Jun;7(3):452-63. doi: 10.1016/j.molonc.2012.11.004. Epub 2012 Dec 21.
• [2] Age-Related Intraneuronal Aggregation of Amyloid- in Endosomes, Mitochondria, Autophagosomes, and Lysosomes.J Alzheimers Dis. 2020;73(1):229-246. doi: 10.3233/JAD-190835.
• [3] Increased expression of ESCO1 is correlated with poor patient survival and its role in human bladder cancer.Tumour Biol. 2016 Apr;37(4):5165-70. doi: 10.1007/s13277-015-4375-1. Epub 2015 Nov 7.
• [4] - but not -secretase proteolysis of APP causes synaptic and memory deficits in a mouse model of dementia.EMBO Mol Med. 2012 Mar;4(3):171-9. doi: 10.1002/emmm.201100195. Epub 2012 Jan 23.
• [5] Cell adhesion molecule-1 shedding induces apoptosis of renal epithelial cells and exacerbates human nephropathies.Am J Physiol Renal Physiol. 2018 Mar 1;314(3):F388-F398. doi: 10.1152/ajprenal.00385.2017. Epub 2017 Oct 25.
• [6] Linkage between EMT and stemness state through molecular association between TWIST1 and NY-ESO1 in esophageal squamouscell carcinoma.Biochimie. 2019 Aug;163:84-93. doi: 10.1016/j.biochi.2019.05.016. Epub 2019 May 31.
• [7] BCL6 degradation caused by the interaction with the C-terminus of pro-HB-EGF induces cyclin D2 expression in gastric cancers.Br J Cancer. 2009 Apr 21;100(8):1320-9. doi: 10.1038/sj.bjc.6605010. Epub 2009 Mar 31.
• [8] Predisposition for TMPRSS2-ERG fusion in prostate cancer by variants in DNA repair genes.Cancer Epidemiol Biomarkers Prev. 2009 Nov;18(11):3030-5. doi: 10.1158/1055-9965.EPI-09-0772. Epub 2009 Oct 27.
• [9] DNA polymerase 5 acetylation by Eso1 is essential for Schizosaccharomyces pombe viability.Int J Mol Med. 2017 Dec;40(6):1907-1913. doi: 10.3892/ijmm.2017.3192. Epub 2017 Oct 16.
• [10] CTF meeting 2012: Translation of the basic understanding of the biology and genetics of NF1, NF2, and schwannomatosis toward the development of effective therapies.Am J Med Genet A. 2014 Mar;164A(3):563-78. doi: 10.1002/ajmg.a.36312. Epub 2014 Jan 17.
• [11] Cytokine-induced killer cells engineered with exogenous T-cell receptors directed against melanoma antigens: enhanced efficacy of effector cells endowed with a double mechanism of tumor recognition.Hum Gene Ther. 2015 Apr;26(4):220-31. doi: 10.1089/hum.2014.112. Epub 2015 Apr 13.
• [12] Evidence that intramolecular associations between presenilin domains are obligatory for endoproteolytic processing.J Biol Chem. 1999 May 14;274(20):13818-23. doi: 10.1074/jbc.274.20.13818.
• [13] Characterization and utilization of an international neurofibromatosis web-based, patient-entered registry: An observational study.PLoS One. 2017 Jun 23;12(6):e0178639. doi: 10.1371/journal.pone.0178639. eCollection 2017.
• [14] NRBF2 is involved in the autophagic degradation process of APP-CTFs in Alzheimer disease models.Autophagy. 2017;13(12):2028-2040. doi: 10.1080/15548627.2017.1379633.
• [15] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [16] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [17] 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.
• [18] Anti-oncogenic and pro-differentiation effects of clorgyline, a monoamine oxidase A inhibitor, on high grade prostate cancer cells. BMC Med Genomics. 2009 Aug 20;2:55. doi: 10.1186/1755-8794-2-55.
• [19] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [20] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [21] 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.
• [22] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [23] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [24] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [25] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.