Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZZ4P2Z)

• DOT Name: RING1 and YY1-binding protein (RYBP)
• Synonyms: Apoptin-associating protein 1; APAP-1; Death effector domain-associated factor; DED-associated factor; YY1 and E4TF1-associated factor 1
• Gene Name: RYBP
• Related Disease:
  Adult glioblastoma
  Glioblastoma multiforme
  Breast cancer
  Breast carcinoma
  Classic Hodgkin lymphoma
  Hepatocellular carcinoma
  Lung cancer
  Lung carcinoma
  Neoplasm
  Non-small-cell lung cancer
  Plasma cell myeloma
  Thyroid gland undifferentiated (anaplastic) carcinoma
  Melanoma
  Advanced cancer
• UniProt ID: RYBP_HUMAN
• PDB ID: 3IXS
• Pfam ID: PF17219 ; PF00641
• Sequence:
  MTMGDKKSPTRPKRQAKPAADEGFWDCSVCTFRNSAEAFKCSICDVRKGTSTRKPRINSQ
  LVAQQVAQQYATPPPPKKEKKEKVEKQDKEKPEKDKEISPSVTKKNTNKKTKPKSDILKD
  PPSEANSIQSANATTKTSETNHTSRPRLKNVDRSTAQQLAVTVGNVTVIITDFKEKTRSS
  STSSSTVTSSAGSEQQNQSSSGSESTDKGSSRSSTPKGDMSAVNDESF
• Function: 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-like complex acts via chromatin remodeling and modification of histones; it mediates monoubiquitination of histone H2A 'Lys-119', rendering chromatin heritably changed in its expressibility. Component of a PRC1-like complex that mediates monoubiquitination of histone H2A 'Lys-119' on the X chromosome and is required for normal silencing of one copy of the X chromosome in XX females. May stimulate ubiquitination of histone H2A 'Lys-119' by recruiting the complex to target sites. Inhibits ubiquitination and subsequent degradation of TP53, and thereby plays a role in regulating transcription of TP53 target genes. May also regulate the ubiquitin-mediated proteasomal degradation of other proteins like FANK1 to regulate apoptosis. May be implicated in the regulation of the transcription as a repressor of the transcriptional activity of E4TF1. May bind to DNA. May play a role in the repression of tumor growth and metastasis in breast cancer by down-regulating SRRM3.
• Tissue Specificity: Down-regulated in breast cancer tissues and in several breast cancer cell lines (at protein level) . Widely expressed with highest levels in lymphoid tissues and placenta.
• KEGG Pathway: Polycomb repressive complex (hsa03083)
• Reactome Pathway:
  Transcriptional Regulation by E2F6 (R-HSA-8953750)
  RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known (R-HSA-8939243)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Definitive	Altered Expression	[1]
Glioblastoma multiforme	DISK8246	Definitive	Altered Expression	[1]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[2]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[2]
Classic Hodgkin lymphoma	DISV1LU6	Strong	Altered Expression	[3]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[4]
Lung cancer	DISCM4YA	Strong	Altered Expression	[5]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[5]
Neoplasm	DISZKGEW	Strong	Biomarker	[6]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[7]
Plasma cell myeloma	DIS0DFZ0	Strong	Altered Expression	[8]
Thyroid gland undifferentiated (anaplastic) carcinoma	DISYBB1W	Strong	Biomarker	[9]
Melanoma	DIS1RRCY	moderate	Biomarker	[10]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of RING1 and YY1-binding protein (RYBP).	[11]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of RING1 and YY1-binding protein (RYBP).	[12]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of RING1 and YY1-binding protein (RYBP).	[13]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of RING1 and YY1-binding protein (RYBP).	[14]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of RING1 and YY1-binding protein (RYBP).	[15]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of RING1 and YY1-binding protein (RYBP).	[16]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of RING1 and YY1-binding protein (RYBP).	[17]
Selenium	DM25CGV	Approved	Selenium decreases the expression of RING1 and YY1-binding protein (RYBP).	[18]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of RING1 and YY1-binding protein (RYBP).	[19]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of RING1 and YY1-binding protein (RYBP).	[20]
Cocaine	DMSOX7I	Approved	Cocaine increases the expression of RING1 and YY1-binding protein (RYBP).	[21]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of RING1 and YY1-binding protein (RYBP).	[22]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of RING1 and YY1-binding protein (RYBP).	[18]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of RING1 and YY1-binding protein (RYBP).	[23]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of RING1 and YY1-binding protein (RYBP).	[24]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of RING1 and YY1-binding protein (RYBP).	[26]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of RING1 and YY1-binding protein (RYBP).	[27]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of RING1 and YY1-binding protein (RYBP).	[28]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of RING1 and YY1-binding protein (RYBP).	[29]
AHPN	DM8G6O4	Investigative	AHPN decreases the expression of RING1 and YY1-binding protein (RYBP).	[30]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of RING1 and YY1-binding protein (RYBP).	[25]

References

• [1] Generation of Rybp homozygous knockout murine ES cell line GIBHe001-A-1 by using CRISPR/Cas9 technology.Stem Cell Res. 2019 Dec;41:101638. doi: 10.1016/j.scr.2019.101638. Epub 2019 Oct 26.
• [2] RING1 and YY1 binding protein suppresses breast cancer growth and metastasis.Int J Oncol. 2016 Dec;49(6):2442-2452. doi: 10.3892/ijo.2016.3718. Epub 2016 Oct 5.
• [3] Variability in the expression of polycomb proteins in different normal and tumoral tissues. A pilot study using tissue microarrays.Mod Pathol. 2006 May;19(5):684-94. doi: 10.1038/modpathol.3800577.
• [4] MicroRNA-769-5p contributes to the proliferation, migration and invasion of hepatocellular carcinoma cells by attenuating RYBP.Biomed Pharmacother. 2019 Oct;118:109343. doi: 10.1016/j.biopha.2019.109343. Epub 2019 Aug 13.
• [5] RYBP Inhibits Progression and Metastasis of Lung Cancer by Suppressing EGFR Signaling and Epithelial-Mesenchymal Transition.Transl Oncol. 2017 Apr;10(2):280-287. doi: 10.1016/j.tranon.2017.01.004. Epub 2017 Feb 28.
• [6] ETS1 targets RYBP transcription to inhibit tumor cell proliferation.Biochem Biophys Res Commun. 2019 Feb 12;509(3):810-816. doi: 10.1016/j.bbrc.2019.01.006. Epub 2019 Jan 10.
• [7] RYBP predicts survival of patients with non-small cell lung cancer and regulates tumor cell growth and the response to chemotherapy.Cancer Lett. 2015 Dec 28;369(2):386-95. doi: 10.1016/j.canlet.2015.09.003. Epub 2015 Sep 21.
• [8] Classical Hodgkin's lymphoma shows epigenetic features of abortive plasma cell differentiation.Haematologica. 2011 Jun;96(6):863-70. doi: 10.3324/haematol.2010.031138. Epub 2011 Mar 10.
• [9] Overexpression of RYBP inhibits proliferation, invasion, and chemoresistance to cisplatin in anaplastic thyroid cancer cells via the EGFR pathway.J Biochem Mol Toxicol. 2019 Feb;33(2):e22241. doi: 10.1002/jbt.22241. Epub 2018 Nov 15.
• [10] YY1 regulates melanoma tumorigenesis through a miR-9~RYBP axis.J Exp Clin Cancer Res. 2015 Jun 24;34(1):66. doi: 10.1186/s13046-015-0177-y.
• [11] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [12] 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.
• [13] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [14] 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.
• [15] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [16] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [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] 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.
• [19] 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.
• [20] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [21] Gene expression in human hippocampus from cocaine abusers identifies genes which regulate extracellular matrix remodeling. PLoS One. 2007 Nov 14;2(11):e1187. doi: 10.1371/journal.pone.0001187.
• [22] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [23] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [24] 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.
• [25] 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.
• [26] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [27] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [28] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [29] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [30] ST1926, a novel and orally active retinoid-related molecule inducing apoptosis in myeloid leukemia cells: modulation of intracellular calcium homeostasis. Blood. 2004 Jan 1;103(1):194-207.