Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLRU8YF)

• DOT Name: ETS-related transcription factor Elf-5 (ELF5)
• Synonyms: E74-like factor 5; Epithelium-restricted ESE-1-related Ets factor; Epithelium-specific Ets transcription factor 2; ESE-2
• Gene Name: ELF5
• Related Disease:
  Acute myelogenous leukaemia
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Chromosomal disorder
  Clear cell renal carcinoma
  Cystic fibrosis
  Eclampsia
  Endometrial carcinoma
  Epithelial ovarian cancer
  Kidney cancer
  Neoplasm
  Ovarian cancer
  Prostate cancer
  Prostate carcinoma
  Pulmonary disease
  Renal carcinoma
  Renal cell carcinoma
  Carcinoma
  Fetal growth restriction
  Asthma
• UniProt ID: ELF5_HUMAN
• PDB ID: 1WWX
• Pfam ID: PF00178 ; PF02198
• Sequence:
  MPSLPHSHRVMLDSVTHSTFLPNASFCDPLMSWTDLFSNEEYYPAFEHQTACDSYWTSVH
  PEYWTKRHVWEWLQFCCDQYKLDTNCISFCNFNISGLQLCSMTQEEFVEAAGLCGEYLYF
  ILQNIRTQGYSFFNDAEESKATIKDYADSNCLKTSGIKSQDCHSHSRTSLQSSHLWEFVR
  DLLLSPEENCGILEWEDREQGIFRVVKSEALAKMWGQRKKNDRMTYEKLSRALRYYYKTG
  ILERVDRRLVYKFGKNAHGWQEDKL
• Function: Transcriptionally activator that may play a role in regulating the later stages of keratinocytes terminal differentiation; Isoform 2 binds to DNA sequences containing the consensus nucleotide core sequence GGA[AT]. Transcriptionally activates SPRR2A and the parotid gland-specific PSP promoters.
• Tissue Specificity: Expressed exclusively in tissues with a high content of epithelial cells. Highly expressed in salivary gland, mammary gland, kidney and prostate. Weakly expressed in placenta and lung. Isoform 1 and isoform 2 are differentially expressed in different tissues. In the kidney, only isoform 1 was expressed, while prostate expressed both isoforms, with levels of isoform 2 being higher. Expression is up-regulated during keratinocyte differentiation. Several epithelial carcinoma cell lines showed lack of expression.
• KEGG Pathway: Prolactin sig.ling pathway (hsa04917)

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[3]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[3]
Chromosomal disorder	DISM5BB5	Strong	Altered Expression	[4]
Clear cell renal carcinoma	DISBXRFJ	Strong	Altered Expression	[5]
Cystic fibrosis	DIS2OK1Q	Strong	Genetic Variation	[3]
Eclampsia	DISWPO8U	Strong	Biomarker	[6]
Endometrial carcinoma	DISXR5CY	Strong	Altered Expression	[7]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[8]
Kidney cancer	DISBIPKM	Strong	Altered Expression	[5]
Neoplasm	DISZKGEW	Strong	Biomarker	[9]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[8]
Prostate cancer	DISF190Y	Strong	Altered Expression	[10]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[10]
Pulmonary disease	DIS6060I	Strong	Biomarker	[3]
Renal carcinoma	DISER9XT	Strong	Altered Expression	[5]
Renal cell carcinoma	DISQZ2X8	Strong	Altered Expression	[5]
Carcinoma	DISH9F1N	moderate	Biomarker	[11]
Fetal growth restriction	DIS5WEJ5	moderate	Altered Expression	[12]
Asthma	DISW9QNS	Limited	Genetic Variation	[13]

9 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 ETS-related transcription factor Elf-5 (ELF5).	[14]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of ETS-related transcription factor Elf-5 (ELF5).	[15]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of ETS-related transcription factor Elf-5 (ELF5).	[16]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of ETS-related transcription factor Elf-5 (ELF5).	[17]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of ETS-related transcription factor Elf-5 (ELF5).	[18]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the expression of ETS-related transcription factor Elf-5 (ELF5).	[19]
Promegestone	DMK4S8I	Approved	Promegestone increases the expression of ETS-related transcription factor Elf-5 (ELF5).	[20]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of ETS-related transcription factor Elf-5 (ELF5).	[23]
ORG2058	DMH1M6N	Investigative	ORG2058 increases the expression of ETS-related transcription factor Elf-5 (ELF5).	[20]

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 decreases the methylation of ETS-related transcription factor Elf-5 (ELF5).	[21]
SB-431542	DM0YOXQ	Preclinical	SB-431542 decreases the methylation of ETS-related transcription factor Elf-5 (ELF5).	[22]

References

• [1] EWSR1/ELF5 induces acute myeloid leukemia by inhibiting p53/p21 pathway.Cancer Sci. 2016 Dec;107(12):1745-1754. doi: 10.1111/cas.13080. Epub 2016 Nov 25.
• [2] A new Elf5(Cre)(ERT)(2-)(GFP) BAC transgenic mouse model for tracing Elf5 cell lineages in adult tissues.FEBS Lett. 2019 May;593(10):1030-1039. doi: 10.1002/1873-3468.13390. Epub 2019 May 1.
• [3] Coordinate regulation of ELF5 and EHF at the chr11p13 CF modifier region.J Cell Mol Med. 2019 Nov;23(11):7726-7740. doi: 10.1111/jcmm.14646. Epub 2019 Sep 26.
• [4] Novel TNS3-MAP3K3 and ZFPM2-ELF5 fusion genes identified by RNA sequencing in multicystic mesothelioma with t(7;17)(p12;q23) and t(8;11)(q23;p13).Cancer Lett. 2015 Feb 28;357(2):502-9. doi: 10.1016/j.canlet.2014.12.002. Epub 2014 Dec 4.
• [5] The Ets transcription factor ELF5 functions as a tumor suppressor in the kidney.Twin Res Hum Genet. 2011 Aug;14(4):316-22. doi: 10.1375/twin.14.4.316.
• [6] ELF5-enforced transcriptional networks define an epigenetically regulated trophoblast stem cell compartment in the human placenta.Hum Mol Genet. 2010 Jun 15;19(12):2456-67. doi: 10.1093/hmg/ddq128. Epub 2010 Mar 30.
• [7] Expression of ELF5 in endometrial carcinoma tissues and its clinical significance.Oncol Lett. 2018 Sep;16(3):3473-3480. doi: 10.3892/ol.2018.9093. Epub 2018 Jul 5.
• [8] ELF5 in epithelial ovarian carcinoma tissues and biological behavior in ovarian carcinoma cells.Oncol Rep. 2017 Mar;37(3):1412-1418. doi: 10.3892/or.2017.5418. Epub 2017 Feb 2.
• [9] Overexpression of E74-Like Factor 5 (ELF5) Inhibits Migration and Invasion of Ovarian Cancer Cells.Med Sci Monit. 2019 Jan 30;25:856-865. doi: 10.12659/MSM.913058.
• [10] ELF5-Mediated AR Activation Regulates Prostate Cancer Progression.Sci Rep. 2017 Mar 13;7:42759. doi: 10.1038/srep42759.
• [11] Effect of the normal mammary differentiation regulator ELF5 upon clinical outcomes of triple negative breast cancers patients.Breast Cancer. 2018 Jul;25(4):489-496. doi: 10.1007/s12282-018-0842-z. Epub 2018 Feb 2.
• [12] ELF5 transcription factor expression during gestation in humans and rats - an immunohistochemical analysis.J Matern Fetal Neonatal Med. 2017 Jun;30(11):1261-1266. doi: 10.1080/14767058.2016.1210596. Epub 2016 Aug 2.
• [13] Polymorphisms of EHF-ELF5 genomic region and its association with pediatric asthma in the Taiwanese population.J Microbiol Immunol Infect. 2016 Dec;49(6):879-884. doi: 10.1016/j.jmii.2014.11.016. Epub 2014 Dec 11.
• [14] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [15] Epidermal growth factor receptor signalling in human breast cancer cells operates parallel to estrogen receptor alpha signalling and results in tamoxifen insensitive proliferation. BMC Cancer. 2014 Apr 23;14:283.
• [16] 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.
• [17] Genistein disrupts glucocorticoid receptor signaling in human uterine endometrial Ishikawa cells. Environ Health Perspect. 2015 Jan;123(1):80-7. doi: 10.1289/ehp.1408437. Epub 2014 Aug 19.
• [18] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [19] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [20] The antiproliferative effects of progestins in T47D breast cancer cells are tempered by progestin induction of the ETS transcription factor Elf5. Mol Endocrinol. 2010 Jul;24(7):1380-92. doi: 10.1210/me.2009-0516. Epub 2010 Jun 2.
• [21] 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.
• [22] Activin/nodal signaling switches the terminal fate of human embryonic stem cell-derived trophoblasts. J Biol Chem. 2015 Apr 3;290(14):8834-48.
• [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.