Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2PN28R)

• DOT Name: Transcription factor E2F6 (E2F6)
• Synonyms: E2F-6
• Gene Name: E2F6
• Related Disease:
  Adult glioblastoma
  Glioblastoma multiforme
  Acute erythroid leukemia
  Cardiac failure
  Classic Hodgkin lymphoma
  Congestive heart failure
  Dilated cardiomyopathy
  Dilated cardiomyopathy 1A
  Endometrial carcinoma
  Epithelial ovarian cancer
  Hepatocellular carcinoma
  Neoplasm
  Non-small-cell lung cancer
  Osteosarcoma
  Ovarian cancer
  Ovarian neoplasm
  Stomach cancer
  Triple negative breast cancer
  Thyroid gland papillary carcinoma
  Breast cancer
  Breast carcinoma
  Breast neoplasm
• UniProt ID: E2F6_HUMAN
• Pfam ID: PF16421 ; PF02319
• Sequence:
  MSQQRPARKLPSLLLDPTEETVRRRCRDPINVEGLLPSKIRINLEDNVQYVSMRKALKVK
  RPRFDVSLVYLTRKFMDLVRSAPGGILDLNKVATKLGVRKRRVYDITNVLDGIDLVEKKS
  KNHIRWIGSDLSNFGAVPQQKKLQEELSDLSAMEDALDELIKDCAQQLFELTDDKENERL
  AYVTYQDIHSIQAFHEQIVIAVKAPAETRLDVPAPREDSITVHIRSTNGPIDVYLCEVEQ
  GQTSNKRSEGVGTSSSESTHPEGPEEEENPQQSEELLEVSN
• Function: Inhibitor of E2F-dependent transcription. Binds DNA cooperatively with DP proteins through the E2 recognition site, 5'-TTTC[CG]CGC-3'. Has a preference for the 5'-TTTCCCGC-3' E2F recognition site. E2F6 lacks the transcriptional activation and pocket protein binding domains. Appears to regulate a subset of E2F-dependent genes whose products are required for entry into the cell cycle but not for normal cell cycle progression. Represses expression of some meiosis-specific genes, including SLC25A31/ANT4. May silence expression via the recruitment of a chromatin remodeling complex containing histone H3-K9 methyltransferase activity. Overexpression delays the exit of cells from the S-phase.
• Tissue Specificity: Expressed in all tissues examined. Highest levels in placenta, skeletal muscle, heart, ovary, kidney, small intestine and spleen.
• KEGG Pathway: Polycomb repressive complex (hsa03083)
• Reactome Pathway:
  Transcriptional Regulation by E2F6 (R-HSA-8953750)
  G1/S-Specific Transcription (R-HSA-69205)

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Definitive	Biomarker	[1]
Glioblastoma multiforme	DISK8246	Definitive	Biomarker	[1]
Acute erythroid leukemia	DISZFC1O	Strong	Biomarker	[2]
Cardiac failure	DISDC067	Strong	Biomarker	[3]
Classic Hodgkin lymphoma	DISV1LU6	Strong	Altered Expression	[4]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[3]
Dilated cardiomyopathy	DISX608J	Strong	Biomarker	[3]
Dilated cardiomyopathy 1A	DIS0RK9Z	Strong	Biomarker	[3]
Endometrial carcinoma	DISXR5CY	Strong	Biomarker	[5]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[6]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[7]
Neoplasm	DISZKGEW	Strong	Altered Expression	[8]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[9]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[10]
Ovarian cancer	DISZJHAP	Strong	Altered Expression	[6]
Ovarian neoplasm	DISEAFTY	Strong	Altered Expression	[6]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[11]
Triple negative breast cancer	DISAMG6N	Strong	Altered Expression	[12]
Thyroid gland papillary carcinoma	DIS48YMM	Disputed	Altered Expression	[13]
Breast cancer	DIS7DPX1	Limited	Biomarker	[8]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[8]
Breast neoplasm	DISNGJLM	Limited	Altered Expression	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Transcription factor E2F6 (E2F6).	[14]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Transcription factor E2F6 (E2F6).	[18]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide affects the methylation of Transcription factor E2F6 (E2F6).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Transcription factor E2F6 (E2F6).	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Transcription factor E2F6 (E2F6).	[15]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Transcription factor E2F6 (E2F6).	[16]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Transcription factor E2F6 (E2F6).	[17]
Decitabine	DMQL8XJ	Approved	Decitabine decreases the expression of Transcription factor E2F6 (E2F6).	[20]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Transcription factor E2F6 (E2F6).	[21]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Transcription factor E2F6 (E2F6).	[21]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Transcription factor E2F6 (E2F6).	[23]
Eugenol	DM7US1H	Patented	Eugenol increases the expression of Transcription factor E2F6 (E2F6).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Transcription factor E2F6 (E2F6).	[25]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Transcription factor E2F6 (E2F6).	[26]

References

• [1] Genome-Wide CRISPR-Cas9 Screening Identifies NF-B/E2F6 Responsible for EGFRvIII-Associated Temozolomide Resistance in Glioblastoma.Adv Sci (Weinh). 2019 Jul 24;6(17):1900782. doi: 10.1002/advs.201900782. eCollection 2019 Sep 4.
• [2] Functional interrelationship between TFII-I and E2F transcription factors at specific cell cycle gene loci.J Cell Biochem. 2018 Jan;119(1):712-722. doi: 10.1002/jcb.26235. Epub 2017 Jul 31.
• [3] E2F6 Impairs Glycolysis and Activates BDH1 Expression Prior to Dilated Cardiomyopathy.PLoS One. 2017 Jan 13;12(1):e0170066. doi: 10.1371/journal.pone.0170066. eCollection 2017.
• [4] Abnormal PcG protein expression in Hodgkin's lymphoma. Relation with E2F6 and NFkappaB transcription factors.J Pathol. 2004 Dec;204(5):528-37. doi: 10.1002/path.1661.
• [5] MicroRNA-424/E2F6 feedback loop modulates cell invasion, migration and EMT in endometrial carcinoma.Oncotarget. 2017 Dec 13;8(69):114281-114291. doi: 10.18632/oncotarget.23218. eCollection 2017 Dec 26.
• [6] E2F6 functions as a competing endogenous RNA, and transcriptional repressor, to promote ovarian cancer stemness.Cancer Sci. 2019 Mar;110(3):1085-1095. doi: 10.1111/cas.13920. Epub 2019 Jan 25.
• [7] Promising diagnostic and prognostic value of E2Fs in human hepatocellular carcinoma.Cancer Manag Res. 2019 Feb 19;11:1725-1740. doi: 10.2147/CMAR.S182001. eCollection 2019.
• [8] E2F6 is essential for cell viability in breast cancer cells during replication stress.Turk J Biol. 2019 Oct 14;43(5):293-304. doi: 10.3906/biy-1905-6. eCollection 2019.
• [9] Hypoxia-sensitive LINC01436 is regulated by E2F6 and acts as an oncogene by targeting miR-30a-3p in non-small cell lung cancer.Mol Oncol. 2019 Apr;13(4):840-856. doi: 10.1002/1878-0261.12437. Epub 2019 Jan 30.
• [10] PHC3, a component of the hPRC-H complex, associates with E2F6 during G0 and is lost in osteosarcoma tumors.Oncogene. 2007 Mar 15;26(12):1714-22. doi: 10.1038/sj.onc.1209988. Epub 2006 Sep 25.
• [11] E2F6-mediated lncRNA CASC2 down-regulation predicts poor prognosis and promotes progression in gastric carcinoma.Life Sci. 2019 Sep 1;232:116649. doi: 10.1016/j.lfs.2019.116649. Epub 2019 Jul 10.
• [12] miR-185 suppresses tumor proliferation by directly targeting E2F6 and DNMT1 and indirectly upregulating BRCA1 in triple-negative breast cancer.Mol Cancer Ther. 2014 Dec;13(12):3185-97. doi: 10.1158/1535-7163.MCT-14-0243. Epub 2014 Oct 15.
• [13] DNA copy number gain-mediated lncRNA LINC01061 upregulation predicts poor prognosis and promotes papillary thyroid cancer progression.Biochem Biophys Res Commun. 2018 Sep 10;503(3):1247-1253. doi: 10.1016/j.bbrc.2018.07.032. Epub 2018 Jul 11.
• [14] 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.
• [15] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [16] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [17] 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.
• [18] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [19] Analysis of the transcriptional regulation of cancer-related genes by aberrant DNA methylation of the cis-regulation sites in the promoter region during hepatocyte carcinogenesis caused by arsenic. Oncotarget. 2015 Aug 28;6(25):21493-506. doi: 10.18632/oncotarget.4085.
• [20] The DNA methyltransferase inhibitors azacitidine, decitabine and zebularine exert differential effects on cancer gene expression in acute myeloid leukemia cells. Leukemia. 2009 Jun;23(6):1019-28.
• [21] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [22] 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.
• [23] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [24] 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.
• [25] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [26] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.