Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1XWING)

• DOT Name: Transcription factor E2F5 (E2F5)
• Synonyms: E2F-5
• Gene Name: E2F5
• Related Disease:
  Adult glioblastoma
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Colorectal carcinoma
  Esophageal squamous cell carcinoma
  Glioblastoma multiforme
  Hepatocellular carcinoma
  Hydrocephalus
  Neoplasm
  Neuroblastoma
  Prostate cancer
  Prostate carcinoma
  Retinoblastoma
  Gastric cancer
  Stomach cancer
  Head-neck squamous cell carcinoma
  Non-small-cell lung cancer
• UniProt ID: E2F5_HUMAN
• PDB ID: 5TUV
• Pfam ID: PF16421 ; PF02319
• Sequence:
  MAAAEPASSGQQAPAGQGQGQRPPPQPPQAQAPQPPPPPQLGGAGGGSSRHEKSLGLLTT
  KFVSLLQEAKDGVLDLKAAADTLAVRQKRRIYDITNVLEGIDLIEKKSKNSIQWKGVGAG
  CNTKEVIDRLRYLKAEIEDLELKERELDQQKLWLQQSIKNVMDDSINNRFSYVTHEDICN
  CFNGDTLLAIQAPSGTQLEVPIPEMGQNGQKKYQINLKSHSGPIHVLLINKESSSSKPVV
  FPVPPPDDLTQPSSQSLTPVTPQKSSMATQNLPEQHVSERSQALQQTSATDISSAGSISG
  DIIDELMSSDVFPLLRLSPTPADDYNFNLDDNEGVCDLFDVQILNY
• Function: Transcriptional activator that binds to E2F sites, these sites are present in the promoter of many genes whose products are involved in cell proliferation. May mediate growth factor-initiated signal transduction. It is likely involved in the early responses of resting cells to growth factor stimulation. Specifically required for multiciliate cell differentiation: together with MCIDAS and E2F5, binds and activate genes required for centriole biogenesis.
• KEGG Pathway:
  Cell cycle (hsa04110)
  Cellular senescence (hsa04218)
  TGF-beta sig.ling pathway (hsa04350)
• Reactome Pathway:
  Transcription of E2F targets under negative control by p107 (RBL1) and p130 (RBL2) in complex with HDAC1 (R-HSA-1362300)
  G0 and Early G1 (R-HSA-1538133)
  SMAD2/SMAD3 (R-HSA-2173796)
  Cyclin E associated events during G1/S transition (R-HSA-69202)
  G1/S-Specific Transcription (R-HSA-69205)
  Cyclin D associated events in G1 (R-HSA-69231)
  Cyclin A (R-HSA-69656)
  Transcription of E2F targets under negative control by DREAM complex (R-HSA-1362277)

Molecular Interaction Atlas (MIA) of This DOT

19 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[3]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[3]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[4]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[5]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[6]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[1]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[7]
Hydrocephalus	DISIZUF7	Strong	Biomarker	[8]
Neoplasm	DISZKGEW	Strong	Biomarker	[9]
Neuroblastoma	DISVZBI4	Strong	Biomarker	[2]
Prostate cancer	DISF190Y	Strong	Altered Expression	[10]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[10]
Retinoblastoma	DISVPNPB	Strong	Biomarker	[11]
Gastric cancer	DISXGOUK	moderate	Biomarker	[12]
Stomach cancer	DISKIJSX	moderate	Biomarker	[12]
Head-neck squamous cell carcinoma	DISF7P24	Limited	Biomarker	[13]
Non-small-cell lung cancer	DIS5Y6R9	Limited	Biomarker	[14]

24 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 Transcription factor E2F5 (E2F5).	[15]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Transcription factor E2F5 (E2F5).	[16]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Transcription factor E2F5 (E2F5).	[17]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Transcription factor E2F5 (E2F5).	[18]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Transcription factor E2F5 (E2F5).	[19]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Transcription factor E2F5 (E2F5).	[20]
Arsenic	DMTL2Y1	Approved	Arsenic increases the expression of Transcription factor E2F5 (E2F5).	[21]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Transcription factor E2F5 (E2F5).	[22]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Transcription factor E2F5 (E2F5).	[23]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Transcription factor E2F5 (E2F5).	[24]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Transcription factor E2F5 (E2F5).	[25]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Transcription factor E2F5 (E2F5).	[26]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Transcription factor E2F5 (E2F5).	[27]
Paclitaxel	DMLB81S	Approved	Paclitaxel increases the expression of Transcription factor E2F5 (E2F5).	[28]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Transcription factor E2F5 (E2F5).	[25]
Menthol	DMG2KW7	Approved	Menthol decreases the expression of Transcription factor E2F5 (E2F5).	[29]
Daunorubicin	DMQUSBT	Approved	Daunorubicin increases the expression of Transcription factor E2F5 (E2F5).	[30]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Transcription factor E2F5 (E2F5).	[31]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the expression of Transcription factor E2F5 (E2F5).	[32]
Eugenol	DM7US1H	Patented	Eugenol decreases the expression of Transcription factor E2F5 (E2F5).	[34]
EMODIN	DMAEDQG	Terminated	EMODIN increases the expression of Transcription factor E2F5 (E2F5).	[35]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Transcription factor E2F5 (E2F5).	[36]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Transcription factor E2F5 (E2F5).	[37]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of Transcription factor E2F5 (E2F5).	[38]

1 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 Transcription factor E2F5 (E2F5).	[33]

References

• [1] MicroRNA-129-3p suppresses tumor growth by targeting E2F5 in glioblastoma.Eur Rev Med Pharmacol Sci. 2018 Feb;22(4):1044-1050. doi: 10.26355/eurrev_201802_14387.
• [2] MYCN-induced E2F5 promotes neuroblastoma cell proliferation through regulating cell cycle progression.Biochem Biophys Res Commun. 2019 Mar 26;511(1):35-40. doi: 10.1016/j.bbrc.2019.01.087. Epub 2019 Feb 11.
• [3] Expression patterns of E2F transcription factors and their potential prognostic roles in breast cancer.Oncol Lett. 2018 Jun;15(6):9216-9230. doi: 10.3892/ol.2018.8514. Epub 2018 Apr 17.
• [4] Human E2F5 gene is oncogenic in primary rodent cells and is amplified in human breast tumors.Genes Chromosomes Cancer. 2000 May;28(1):126-30.
• [5] Long noncoding RNA SNHG6 functions as a competing endogenous RNA by sponging miR-181a-5p to regulate E2F5 expression in colorectal cancer.Cancer Manag Res. 2019 Jan 10;11:611-624. doi: 10.2147/CMAR.S182719. eCollection 2019.
• [6] MicroRNA-544 inhibits esophageal squamous cell carcinoma cell proliferation and enhances sensitivity to cisplatin by repressing E2F transcription factor 5.Oncol Lett. 2019 Oct;18(4):4203-4209. doi: 10.3892/ol.2019.10749. Epub 2019 Aug 16.
• [7] The transcription factor FOXN3 inhibits cell proliferation by downregulating E2F5 expression in hepatocellular carcinoma cells.Oncotarget. 2016 Jul 12;7(28):43534-43545. doi: 10.18632/oncotarget.9780.
• [8] A specific, nonproliferative role for E2F-5 in choroid plexus function revealed by gene targeting.Genes Dev. 1998 Apr 15;12(8):1092-8. doi: 10.1101/gad.12.8.1092.
• [9] MicroRNA-32 inhibits the proliferation, migration and invasion of human colon cancer cell lines by targeting E2F transcription factor 5.Eur Rev Med Pharmacol Sci. 2019 May;23(10):4156-4163. doi: 10.26355/eurrev_201905_17918.
• [10] Identification of tumor suppressive role of microRNA-132 and its target gene in tumorigenesis of prostate cancer.Int J Mol Med. 2018 Apr;41(4):2429-2433. doi: 10.3892/ijmm.2018.3421. Epub 2018 Jan 23.
• [11] MiR-613 suppresses retinoblastoma cell proliferation, invasion, and tumor formation by targeting E2F5.Tumour Biol. 2017 Mar;39(3):1010428317691674. doi: 10.1177/1010428317691674.
• [12] miRNA-34a enhances the sensitivity of gastric cancer cells to treatment with paclitaxel by targeting E2F5.Oncol Lett. 2017 Jun;13(6):4837-4842. doi: 10.3892/ol.2017.6041. Epub 2017 Apr 18.
• [13] HPV/E7 induces chemotherapy-mediated tumor suppression by ceramide-dependent mitophagy.EMBO Mol Med. 2017 Aug;9(8):1030-1051. doi: 10.15252/emmm.201607088.
• [14] Transcriptional E2F1/2/5/8 as potential targets and transcriptional E2F3/6/7 as new biomarkers for the prognosis of human lung carcinoma.Aging (Albany NY). 2018 May 11;10(5):973-987. doi: 10.18632/aging.101441.
• [15] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [16] 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.
• [17] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [18] 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.
• [19] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [20] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [21] Application of cDNA microarray to the study of arsenic-induced liver diseases in the population of Guizhou, China. Toxicol Sci. 2001 Jan;59(1):185-92.
• [22] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [23] 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.
• [24] Arsenic trioxide induces different gene expression profiles of genes related to growth and apoptosis in glioma cells dependent on the p53 status. Mol Biol Rep. 2008 Sep;35(3):421-9.
• [25] 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.
• [26] 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.
• [27] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [28] Effects of paclitaxel on proliferation and apoptosis in human acute myeloid leukemia HL-60 cells. Acta Pharmacol Sin. 2004 Mar;25(3):378-84.
• [29] Repurposing L-menthol for systems medicine and cancer therapeutics? L-menthol induces apoptosis through caspase 10 and by suppressing HSP90. OMICS. 2016 Jan;20(1):53-64.
• [30] Daunorubicin-induced variations in gene transcription: commitment to proliferation arrest, senescence and apoptosis. Biochem J. 2003 Jun 15;372(Pt 3):703-11. doi: 10.1042/BJ20021950.
• [31] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [32] Gene expression profiling identifies activating transcription factor 3 as a novel contributor to the proapoptotic effect of curcumin. Mol Cancer Ther. 2005 Feb;4(2):233-41.
• [33] 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.
• [34] Eugenol causes melanoma growth suppression through inhibition of E2F1 transcriptional activity. J Biol Chem. 2005 Feb 18;280(7):5812-9. doi: 10.1074/jbc.M411429200. Epub 2004 Dec 1.
• [35] Gene expression alteration during redox-dependent enhancement of arsenic cytotoxicity by emodin in HeLa cells. Cell Res. 2005 Jul;15(7):511-22.
• [36] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [37] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [38] 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.