Details of Drug Off-Target (DOT)

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

• DOT Name: E3 ubiquitin-protein ligase RING2 (RNF2)
• Synonyms: EC 2.3.2.27; Huntingtin-interacting protein 2-interacting protein 3; HIP2-interacting protein 3; Protein DinG; RING finger protein 1B; RING1b; RING finger protein 2; RING finger protein BAP-1; RING-type E3 ubiquitin transferase RING2
• Gene Name: RNF2
• Related Disease:
  Melanoma
  Metastatic malignant neoplasm
  Acute monocytic leukemia
  Acute myelogenous leukaemia
  Adult lymphoma
  Benign prostatic hyperplasia
  Bladder cancer
  Breast cancer
  Breast carcinoma
  Carcinoma of esophagus
  Cholangiocarcinoma
  Digestive system neoplasm
  Epithelial ovarian cancer
  Esophageal cancer
  Esophageal squamous cell carcinoma
  Ewing sarcoma
  Intrahepatic cholangiocarcinoma
  Lung cancer
  Lung carcinoma
  Luo-Schoch-Yamamoto syndrome
  Neoplasm
  Neoplasm of esophagus
  Ovarian cancer
  Ovarian neoplasm
  Pancreatic cancer
  Pediatric lymphoma
  Prostate cancer
  Prostate carcinoma
  Rheumatoid arthritis
  Squamous cell carcinoma
  Transitional cell carcinoma
  Urothelial carcinoma
  Uveal Melanoma
  Coloboma
  Hepatocellular carcinoma
  HIV infectious disease
  Matthew-Wood syndrome
  Neurodevelopmental disorder
  Pancreatic ductal carcinoma
  Advanced cancer
  Angelman syndrome
  Clear cell renal carcinoma
  Cutaneous melanoma
  Cutaneous squamous cell carcinoma
  Gastric cancer
  Lymphoma
  Stomach cancer
• UniProt ID: RING2_HUMAN
• PDB ID: 2H0D; 3GS2; 3H8H; 3IXS; 3RPG; 4R8P; 4S3O; 6WI7; 6WI8; 7ND1; 8GRM
• EC Number: 2.3.2.27
• Pfam ID: PF16207 ; PF13923
• Sequence:
  MSQAVQTNGTQPLSKTWELSLYELQRTPQEAITDGLEIVVSPRSLHSELMCPICLDMLKN
  TMTTKECLHRFCADCIITALRSGNKECPTCRKKLVSKRSLRPDPNFDALISKIYPSRDEY
  EAHQERVLARINKHNNQQALSHSIEEGLKIQAMNRLQRGKKQQIENGSGAEDNGDSSHCS
  NASTHSNQEAGPSNKRTKTSDDSGLELDNNNAAMAIDPVMDGASEIELVFRPHPTLMEKD
  DSAQTRYIKTSGNATVDHLSKYLAVRLALEELRSKGESNQMNLDTASEKQYTIYIATASG
  QFTVLNGSFSLELVSEKYWKVNKPMELYYAPTKEHK
• Function: E3 ubiquitin-protein ligase that mediates monoubiquitination of 'Lys-119' of histone H2A (H2AK119Ub), thereby playing a central role in histone code and gene regulation. H2AK119Ub gives a specific tag for epigenetic transcriptional repression and participates in X chromosome inactivation of female mammals. May be involved in the initiation of both imprinted and random X inactivation. Essential component of a Polycomb group (PcG) multiprotein PRC1-like complex, a complex class required to maintain the transcriptionally repressive state of many genes, including Hox genes, throughout development. PcG PRC1 complex acts via chromatin remodeling and modification of histones, rendering chromatin heritably changed in its expressibility. E3 ubiquitin-protein ligase activity is enhanced by BMI1/PCGF4. Acts as the main E3 ubiquitin ligase on histone H2A of the PRC1 complex, while RING1 may rather act as a modulator of RNF2/RING2 activity (Probable). Association with the chromosomal DNA is cell-cycle dependent. In resting B- and T-lymphocytes, interaction with AURKB leads to block its activity, thereby maintaining transcription in resting lymphocytes. Also acts as a negative regulator of autophagy by mediating ubiquitination of AMBRA1, leading to its subsequent degradation.
• KEGG Pathway: Polycomb repressive complex (hsa03083)
• Reactome Pathway:
  SUMOylation of DNA damage response and repair proteins (R-HSA-3108214)
  SUMOylation of transcription cofactors (R-HSA-3899300)
  SUMOylation of chromatin organization proteins (R-HSA-4551638)
  SUMOylation of RNA binding proteins (R-HSA-4570464)
  SUMOylation of DNA methylation proteins (R-HSA-4655427)
  RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known (R-HSA-8939243)
  Regulation of PTEN gene transcription (R-HSA-8943724)
  Transcriptional Regulation by E2F6 (R-HSA-8953750)
  Oxidative Stress Induced Senescence (R-HSA-2559580)

Molecular Interaction Atlas (MIA) of This DOT

47 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Melanoma	DIS1RRCY	Definitive	Altered Expression	[1]
Metastatic malignant neoplasm	DIS86UK6	Definitive	Biomarker	[1]
Acute monocytic leukemia	DIS28NEL	Strong	Altered Expression	[2]
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[2]
Adult lymphoma	DISK8IZR	Strong	Altered Expression	[3]
Benign prostatic hyperplasia	DISI3CW2	Strong	Altered Expression	[4]
Bladder cancer	DISUHNM0	Strong	Altered Expression	[5]
Breast cancer	DIS7DPX1	Strong	Biomarker	[6]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[7]
Carcinoma of esophagus	DISS6G4D	Strong	Biomarker	[8]
Cholangiocarcinoma	DIS71F6X	Strong	Biomarker	[9]
Digestive system neoplasm	DISPOJCT	Strong	Altered Expression	[10]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[11]
Esophageal cancer	DISGB2VN	Strong	Biomarker	[8]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[12]
Ewing sarcoma	DISQYLV3	Strong	Biomarker	[13]
Intrahepatic cholangiocarcinoma	DIS6GOC8	Strong	Genetic Variation	[14]
Lung cancer	DISCM4YA	Strong	Genetic Variation	[14]
Lung carcinoma	DISTR26C	Strong	Genetic Variation	[14]
Luo-Schoch-Yamamoto syndrome	DISFRW0B	Strong	Autosomal dominant	[15]
Neoplasm	DISZKGEW	Strong	Biomarker	[16]
Neoplasm of esophagus	DISOLKAQ	Strong	Biomarker	[8]
Ovarian cancer	DISZJHAP	Strong	Altered Expression	[11]
Ovarian neoplasm	DISEAFTY	Strong	Altered Expression	[11]
Pancreatic cancer	DISJC981	Strong	Altered Expression	[17]
Pediatric lymphoma	DIS51BK2	Strong	Altered Expression	[3]
Prostate cancer	DISF190Y	Strong	Biomarker	[4]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[4]
Rheumatoid arthritis	DISTSB4J	Strong	Biomarker	[18]
Squamous cell carcinoma	DISQVIFL	Strong	Biomarker	[8]
Transitional cell carcinoma	DISWVVDR	Strong	Altered Expression	[5]
Urothelial carcinoma	DISRTNTN	Strong	Altered Expression	[5]
Uveal Melanoma	DISA7ZGL	Strong	Biomarker	[19]
Coloboma	DISP39N5	moderate	Biomarker	[20]
Hepatocellular carcinoma	DIS0J828	moderate	Biomarker	[21]
HIV infectious disease	DISO97HC	moderate	Altered Expression	[22]
Matthew-Wood syndrome	DISA7HR7	moderate	Altered Expression	[23]
Neurodevelopmental disorder	DIS372XH	moderate	Altered Expression	[24]
Pancreatic ductal carcinoma	DIS26F9Q	moderate	Altered Expression	[23]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[7]
Angelman syndrome	DIS4QVXO	Limited	Biomarker	[25]
Clear cell renal carcinoma	DISBXRFJ	Limited	Genetic Variation	[26]
Cutaneous melanoma	DIS3MMH9	Limited	Altered Expression	[1]
Cutaneous squamous cell carcinoma	DIS3LXUG	Limited	Biomarker	[27]
Gastric cancer	DISXGOUK	Limited	Biomarker	[28]
Lymphoma	DISN6V4S	Limited	Altered Expression	[3]
Stomach cancer	DISKIJSX	Limited	Biomarker	[28]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of E3 ubiquitin-protein ligase RING2 (RNF2).	[29]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of E3 ubiquitin-protein ligase RING2 (RNF2).	[38]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of E3 ubiquitin-protein ligase RING2 (RNF2).	[39]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of E3 ubiquitin-protein ligase RING2 (RNF2).	[40]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of E3 ubiquitin-protein ligase RING2 (RNF2).	[30]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of E3 ubiquitin-protein ligase RING2 (RNF2).	[31]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of E3 ubiquitin-protein ligase RING2 (RNF2).	[32]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of E3 ubiquitin-protein ligase RING2 (RNF2).	[33]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of E3 ubiquitin-protein ligase RING2 (RNF2).	[34]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of E3 ubiquitin-protein ligase RING2 (RNF2).	[35]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of E3 ubiquitin-protein ligase RING2 (RNF2).	[36]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of E3 ubiquitin-protein ligase RING2 (RNF2).	[37]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of E3 ubiquitin-protein ligase RING2 (RNF2).	[41]

References

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• [3] A Noncanonical Function of Polycomb Repressive Complexes Promotes Human Cytomegalovirus Lytic DNA Replication and Serves as a Novel Cellular Target for Antiviral Intervention.J Virol. 2019 Apr 17;93(9):e02143-18. doi: 10.1128/JVI.02143-18. Print 2019 May 1.
• [4] Knockdown of RNF2 induces cell cycle arrest and apoptosis in prostate cancer cells through the upregulation of TXNIP.Oncotarget. 2017 Jan 17;8(3):5323-5338. doi: 10.18632/oncotarget.14142.
• [5] Overexpression of RNF2 Is an Independent Predictor of Outcome in Patients with Urothelial Carcinoma of the Bladder Undergoing Radical Cystectomy.Sci Rep. 2016 Feb 12;6:20894. doi: 10.1038/srep20894.
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• [11] Reversal of cisplatin resistance by microRNA-139-5p-independent RNF2 downregulation and MAPK inhibition in ovarian cancer.Am J Physiol Cell Physiol. 2018 Aug 1;315(2):C225-C235. doi: 10.1152/ajpcell.00283.2017. Epub 2018 May 2.
• [12] Association between RNF2+P-AKT expression in pretreatment biopsy specimens, and poor survival following radiotherapy in patients with esophageal squamous cell carcinoma.Oncol Lett. 2019 Oct;18(4):3734-3742. doi: 10.3892/ol.2019.10727. Epub 2019 Aug 7.
• [13] RING1B contributes to Ewing sarcoma development by repressing the NaV1.6 sodium channel and the NF-B pathway, independently of the fusion oncoprotein.Oncotarget. 2016 Jul 19;7(29):46283-46300. doi: 10.18632/oncotarget.10092.
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• [17] Hypoxia induces TWIST-activated epithelial-mesenchymal transition and proliferation of pancreatic cancer cells invitro and in nude mice.Cancer Lett. 2016 Dec 1;383(1):73-84. doi: 10.1016/j.canlet.2016.09.027. Epub 2016 Sep 28.
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• [20] Bcl6a function is required during optic cup formation to prevent p53-dependent apoptosis and colobomata.Hum Mol Genet. 2013 Sep 1;22(17):3568-82. doi: 10.1093/hmg/ddt211. Epub 2013 May 12.
• [21] Down-regulation of salt-inducible kinase 1 (SIK1) is mediated by RNF2 in hepatocarcinogenesis.Oncotarget. 2017 Jan 10;8(2):3144-3155. doi: 10.18632/oncotarget.13673.
• [22] The level of DING proteins is increased in HIV-infected patients: in vitro and in vivo studies.PLoS One. 2012;7(3):e33062. doi: 10.1371/journal.pone.0033062. Epub 2012 Mar 9.
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• [28] Long non-coding RNA LINC00665 gastric cancer tumorigenesis by regulation miR-149-3p/RNF2 axis.Onco Targets Ther. 2019 Aug 28;12:6981-6990. doi: 10.2147/OTT.S214588. eCollection 2019.
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• [32] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [33] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [34] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [35] 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.
• [36] 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.
• [37] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [38] 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.
• [39] 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.
• [40] 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.
• [41] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.