Details of Drug Off-Target (DOT)

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

• DOT Name: RNA polymerase II elongation factor ELL2 (ELL2)
• Gene Name: ELL2
• Related Disease:
  Benign prostatic hyperplasia
  Classic Hodgkin lymphoma
  Clear cell renal carcinoma
  Glioma
  IgA nephropathy
  Plasma cell myeloma
  Prostate cancer
  Prostate carcinoma
  Prostate neoplasm
  Retinoblastoma
  Small lymphocytic lymphoma
  Neoplasm
• UniProt ID: ELL2_HUMAN
• PDB ID: 2E5N; 5JW9; 7OKX; 7OKY
• Pfam ID: PF10390 ; PF07303
• Sequence:
  MAAGGTGGLREEQRYGLSCGRLGQDNITVLHVKLTETAIRALETYQSHKNLIPFRPSIQF
  QGLHGLVKIPKNDPLNEVHNFNFYLSNVGKDNPQGSFDCIQQTFSSSGASQLNCLGFIQD
  KITVCATNDSYQMTRERMTQAEEESRNRSTKVIKPGGPYVGKRVQIRKAPQAVSDTVPER
  KRSTPMNPANTIRKTHSSSTISQRPYRDRVIHLLALKAYKKPELLARLQKDGVNQKDKNS
  LGAILQQVANLNSKDLSYTLKDYVFKELQRDWPGYSEIDRRSLESVLSRKLNPSQNAAGT
  SRSESPVCSSRDAVSSPQKRLLDSEFIDPLMNKKARISHLTNRVPPTLNGHLNPTSEKSA
  AGLPLPPAAAAIPTPPPLPSTYLPISHPPQIVNSNSNSPSTPEGRGTQDLPVDSFSQNDS
  IYEDQQDKYTSRTSLETLPPGSVLLKCPKPMEENHSMSHKKSKKKSKKHKEKDQIKKHDI
  ETIEEKEEDLKREEEIAKLNNSSPNSSGGVKEDCTASMEPSAIELPDYLIKYIAIVSYEQ
  RQNYKDDFNAEYDEYRALHARMETVARRFIKLDAQRKRLSPGSKEYQNVHEEVLQEYQKI
  KQSSPNYHEEKYRCEYLHNKLAHIKRLIGEFDQQQAESWS
• Function: Elongation factor component of the super elongation complex (SEC), a complex required to increase the catalytic rate of RNA polymerase II transcription by suppressing transient pausing by the polymerase at multiple sites along the DNA. Component of the little elongation complex (LEC), a complex required to regulate small nuclear RNA (snRNA) gene transcription by RNA polymerase II and III. Plays a role in immunoglobulin secretion in plasma cells: directs efficient alternative mRNA processing, influencing both proximal poly(A) site choice and exon skipping, as well as immunoglobulin heavy chain (IgH) alternative processing. Probably acts by regulating histone modifications accompanying transition from membrane-specific to secretory IgH mRNA expression.
• KEGG Pathway: Viral life cycle - HIV-1 (hsa03250)
• Reactome Pathway: RNA polymerase II transcribes snRNA genes (R-HSA-6807505)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Benign prostatic hyperplasia	DISI3CW2	Strong	Biomarker	[1]
Classic Hodgkin lymphoma	DISV1LU6	Strong	Genetic Variation	[2]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[3]
Glioma	DIS5RPEH	Strong	Altered Expression	[4]
IgA nephropathy	DISZ8MTK	Strong	Altered Expression	[5]
Plasma cell myeloma	DIS0DFZ0	Strong	Genetic Variation	[6]
Prostate cancer	DISF190Y	Strong	Biomarker	[7]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[7]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[1]
Retinoblastoma	DISVPNPB	Strong	Biomarker	[8]
Small lymphocytic lymphoma	DIS30POX	Strong	Genetic Variation	[2]
Neoplasm	DISZKGEW	Disputed	Altered Expression	[9]

27 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 RNA polymerase II elongation factor ELL2 (ELL2).	[10]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of RNA polymerase II elongation factor ELL2 (ELL2).	[11]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of RNA polymerase II elongation factor ELL2 (ELL2).	[12]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of RNA polymerase II elongation factor ELL2 (ELL2).	[13]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of RNA polymerase II elongation factor ELL2 (ELL2).	[14]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of RNA polymerase II elongation factor ELL2 (ELL2).	[15]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of RNA polymerase II elongation factor ELL2 (ELL2).	[16]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of RNA polymerase II elongation factor ELL2 (ELL2).	[17]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of RNA polymerase II elongation factor ELL2 (ELL2).	[18]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of RNA polymerase II elongation factor ELL2 (ELL2).	[19]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of RNA polymerase II elongation factor ELL2 (ELL2).	[20]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of RNA polymerase II elongation factor ELL2 (ELL2).	[21]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol affects the expression of RNA polymerase II elongation factor ELL2 (ELL2).	[22]
Enzalutamide	DMGL19D	Approved	Enzalutamide decreases the expression of RNA polymerase II elongation factor ELL2 (ELL2).	[23]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of RNA polymerase II elongation factor ELL2 (ELL2).	[24]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of RNA polymerase II elongation factor ELL2 (ELL2).	[23]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of RNA polymerase II elongation factor ELL2 (ELL2).	[18]
Genistein	DM0JETC	Phase 2/3	Genistein affects the expression of RNA polymerase II elongation factor ELL2 (ELL2).	[25]
Phenol	DM1QSM3	Phase 2/3	Phenol increases the expression of RNA polymerase II elongation factor ELL2 (ELL2).	[26]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of RNA polymerase II elongation factor ELL2 (ELL2).	[28]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of RNA polymerase II elongation factor ELL2 (ELL2).	[29]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of RNA polymerase II elongation factor ELL2 (ELL2).	[30]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of RNA polymerase II elongation factor ELL2 (ELL2).	[32]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of RNA polymerase II elongation factor ELL2 (ELL2).	[34]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of RNA polymerase II elongation factor ELL2 (ELL2).	[35]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone increases the expression of RNA polymerase II elongation factor ELL2 (ELL2).	[36]
EPZ-004777	DMLN4V5	Investigative	EPZ-004777 increases the expression of RNA polymerase II elongation factor ELL2 (ELL2).	[37]

3 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 RNA polymerase II elongation factor ELL2 (ELL2).	[27]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of RNA polymerase II elongation factor ELL2 (ELL2).	[31]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of RNA polymerase II elongation factor ELL2 (ELL2).	[33]

References

• [1] Conditional deletion of ELL2 induces murine prostate intraepithelial neoplasia.J Endocrinol. 2017 Nov;235(2):123-136. doi: 10.1530/JOE-17-0112.
• [2] Genome-wide association analysis of chronic lymphocytic leukaemia, Hodgkin lymphoma and multiple myeloma identifies pleiotropic risk loci.Sci Rep. 2017 Jan 23;7:41071. doi: 10.1038/srep41071.
• [3] Long noncoding RNA MRCCAT1 promotes metastasis of clear cell renal cell carcinoma via inhibiting NPR3 and activating p38-MAPK signaling.Mol Cancer. 2017 Jun 28;16(1):111. doi: 10.1186/s12943-017-0681-0.
• [4] Upregulation of long noncoding RNA MRCCAT1 predicts poor prognosis and functions as an oncogene in glioma.Eur Rev Med Pharmacol Sci. 2018 Dec;22(23):8406-8414. doi: 10.26355/eurrev_201812_16539.
• [5] ELL2 Is Downregulated and Associated with Galactose-Deficient IgA1 in IgA Nephropathy.Dis Markers. 2019 Jun 4;2019:2407067. doi: 10.1155/2019/2407067. eCollection 2019.
• [6] The multiple myeloma risk allele at 5q15 lowers ELL2 expression and increases ribosomal gene expression.Nat Commun. 2018 Apr 25;9(1):1649. doi: 10.1038/s41467-018-04082-2.
• [7] ELL2 regulates DNA non-homologous end joining (NHEJ) repair in prostate cancer cells.Cancer Lett. 2018 Feb 28;415:198-207. doi: 10.1016/j.canlet.2017.11.028. Epub 2017 Nov 26.
• [8] Physical and Functional Interactions between ELL2 and RB in the Suppression of Prostate Cancer Cell Proliferation, Migration, and Invasion.Neoplasia. 2017 Mar;19(3):207-215. doi: 10.1016/j.neo.2017.01.001. Epub 2017 Feb 3.
• [9] Regulation of ELL2 stability and polyubiquitination by EAF2 in prostate cancer cells.Prostate. 2018 Nov;78(15):1201-1212. doi: 10.1002/pros.23695. Epub 2018 Jul 15.
• [10] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [11] 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.
• [12] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [13] Toxicogenomics-based prediction of acetaminophen-induced liver injury using human hepatic cell systems. Toxicol Lett. 2016 Jan 5;240(1):50-9.
• [14] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [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] 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.
• [17] 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.
• [18] 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.
• [19] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [20] Cannabidiol enhances cytotoxicity of anti-cancer drugs in human head and neck squamous cell carcinoma. Sci Rep. 2020 Nov 26;10(1):20622. doi: 10.1038/s41598-020-77674-y.
• [21] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [22] The genomic response of Ishikawa cells to bisphenol A exposure is dose- and time-dependent. Toxicology. 2010 Apr 11;270(2-3):137-49. doi: 10.1016/j.tox.2010.02.008. Epub 2010 Feb 17.
• [23] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [24] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [25] Dose- and time-dependent transcriptional response of Ishikawa cells exposed to genistein. Toxicol Sci. 2016 May;151(1):71-87.
• [26] Classification of heavy-metal toxicity by human DNA microarray analysis. Environ Sci Technol. 2007 May 15;41(10):3769-74.
• [27] 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.
• [28] Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.
• [29] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [30] 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.
• [31] 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.
• [32] 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.
• [33] Expression and DNA methylation changes in human breast epithelial cells after bisphenol A exposure. Int J Oncol. 2012 Jul;41(1):369-77.
• [34] 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.
• [35] Sulforaphane-induced apoptosis in human leukemia HL-60 cells through extrinsic and intrinsic signal pathways and altering associated genes expression assayed by cDNA microarray. Environ Toxicol. 2017 Jan;32(1):311-328.
• [36] Identification of genes targeted by the androgen and PKA signaling pathways in prostate cancer cells. Oncogene. 2006 Nov 23;25(55):7311-23.
• [37] Histone methyltransferase DOT1L coordinates AR and MYC stability in prostate cancer. Nat Commun. 2020 Aug 19;11(1):4153. doi: 10.1038/s41467-020-18013-7.