Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3Q25ND)

• DOT Name: Enhancer of polycomb homolog 1 (EPC1)
• Gene Name: EPC1
• Related Disease:
  Acute myelogenous leukaemia
  Adenocarcinoma
  Adult T-cell leukemia/lymphoma
  Esophageal adenocarcinoma
  Familial multiple trichoepithelioma
  Echinococcosis
  Lung cancer
  Lung carcinoma
  Advanced cancer
• UniProt ID: EPC1_HUMAN
• PDB ID: 6NFX
• Pfam ID: PF06752 ; PF10513
• Sequence:
  MSKLSFRARALDASKPLPVFRCEDLPDLHEYASINRAVPQMPTGMEKEEESEHHLQRAIS
  AQQVYGEKRDNMVIPVPEAESNIAYYESIYPGEFKMPKQLIHIQPFSLDAEQPDYDLDSE
  DEVFVNKLKKKMDICPLQFEEMIDRLEKGSGQQPVSLQEAKLLLKEDDELIREVYEYWIK
  KRKNCRGPSLIPSVKQEKRDGSSTNDPYVAFRRRTEKMQTRKNRKNDEASYEKMLKLRRD
  LSRAVTILEMIKRREKSKRELLHLTLEIMEKRYNLGDYNGEIMSEVMAQRQPMKPTYAIP
  IIPITNSSQFKHQEAMDVKEFKVNKQDKADLIRPKRKYEKKPKVLPSSAAATPQQTSPAA
  LPVFNAKDLNQYDFPSSDEEPLSQVLSGSSEAEEDNDPDGPFAFRRKAGCQYYAPHLDQT
  GNWPWTSPKDGGLGDVRYRYCLTTLTVPQRCIGFARRRVGRGGRVLLDRAHSDYDSVFHH
  LDLEMLSSPQHSPVNQFANTSETNTSDKSFSKDLSQILVNIKSCRWRHFRPRTPSLHDSD
  NDELSCRKLYRSINRTGTAQPGTQTCSTSTQSKSSSGSAHFAFTAEQYQQHQQQLALMQK
  QQLAQIQQQQANSNSSTNTSQNLASNQQKSGFRLNIQGLERTLQGFVSKTLDSASAQFAA
  SALVTSEQLMGFKMKDDVVLGIGVNGVLPASGVYKGLHLSSTTPTALVHTSPSTAGSALL
  QPSNITQTSSSHSALSHQVTAANSATTQVLIGNNIRLTVPSSVATVNSIAPINARHIPRT
  LSAVPSSALKLAAAANCQVSKVPSSSSVDSVPRENHESEKPALNNIADNTVAMEVT
• Function: Component of the NuA4 histone acetyltransferase (HAT) complex, a multiprotein complex involved in transcriptional activation of select genes principally by acetylation of nucleosomal histones H4 and H2A. The NuA4 complex plays a direct role in repair of DNA double-strand breaks (DSBs) by promoting homologous recombination (HR). The NuA4 complex is also required for spermatid development by promoting acetylation of histones: histone acetylation is required for histone replacement during the transition from round to elongating spermatids. In the NuA4 complex, EPC1 is required to recruit MBTD1 into the complex.
• KEGG Pathway: ATP-dependent chromatin remodeling (hsa03082)
• Reactome Pathway:
  Transcriptional Regulation by E2F6 (R-HSA-8953750)
  HATs acetylate histones (R-HSA-3214847)

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[1]
Adenocarcinoma	DIS3IHTY	Strong	Genetic Variation	[2]
Adult T-cell leukemia/lymphoma	DIS882XU	Strong	Biomarker	[3]
Esophageal adenocarcinoma	DISODWFP	Strong	Biomarker	[4]
Familial multiple trichoepithelioma	DISKZAUY	Strong	Biomarker	[4]
Echinococcosis	DIS8G3V7	moderate	Biomarker	[5]
Lung cancer	DISCM4YA	moderate	Biomarker	[6]
Lung carcinoma	DISTR26C	moderate	Biomarker	[6]
Advanced cancer	DISAT1Z9	Limited	Genetic Variation	[7]

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 Enhancer of polycomb homolog 1 (EPC1).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Enhancer of polycomb homolog 1 (EPC1).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Enhancer of polycomb homolog 1 (EPC1).	[10]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Enhancer of polycomb homolog 1 (EPC1).	[11]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of Enhancer of polycomb homolog 1 (EPC1).	[13]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Enhancer of polycomb homolog 1 (EPC1).	[14]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Enhancer of polycomb homolog 1 (EPC1).	[15]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Enhancer of polycomb homolog 1 (EPC1).	[16]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Enhancer of polycomb homolog 1 (EPC1).	[19]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Enhancer of polycomb homolog 1 (EPC1).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Enhancer of polycomb homolog 1 (EPC1).	[12]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Enhancer of polycomb homolog 1 (EPC1).	[17]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Enhancer of polycomb homolog 1 (EPC1).	[18]

References

• [1] Enhancers of Polycomb EPC1 and EPC2 sustain the oncogenic potential of MLL leukemia stem cells.Leukemia. 2014 May;28(5):1081-91. doi: 10.1038/leu.2013.316. Epub 2013 Oct 29.
• [2] Wnt/-Catenin Signaling Activation beyond Robust Nuclear -Catenin Accumulation in Nondysplastic Barrett's Esophagus: Regulation via Dickkopf-1.Neoplasia. 2015 Jul;17(7):598-611. doi: 10.1016/j.neo.2015.07.006.
• [3] Alteration of enhancer of polycomb 1 at 10p11.2 is one of the genetic events leading to development of adult T-cell leukemia/lymphoma.Genes Chromosomes Cancer. 2009 Sep;48(9):768-76. doi: 10.1002/gcc.20681.
• [4] In-depth characterization of the Wnt-signaling/-catenin pathway in an in vitro model of Barrett's sequence.BMC Gastroenterol. 2019 Mar 6;19(1):38. doi: 10.1186/s12876-019-0957-5.
• [5] Identification of a diagnostic antibody-binding region on the immunogenic protein EpC1 from Echinococcus granulosus and its application in population screening for cystic echinococcosis.Clin Exp Immunol. 2007 Jul;149(1):80-6. doi: 10.1111/j.1365-2249.2007.03386.x. Epub 2007 Apr 2.
• [6] RNA interference targeting enhancer of polycomb1 exerts anti-tumor effects in lung cancer.Int J Clin Exp Pathol. 2015 Jan 1;8(1):361-7. eCollection 2015.
• [7] Ossifying fibromyxoid tumor: morphology, genetics, and differential diagnosis.Ann Diagn Pathol. 2016 Feb;20:52-8. doi: 10.1016/j.anndiagpath.2015.11.002. Epub 2015 Dec 2.
• [8] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [9] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [12] 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.
• [13] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [14] 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.
• [15] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [16] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [17] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [18] 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.
• [19] 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.
• [20] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.