Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT12W2MK)

• DOT Name: Retinoblastoma-binding protein 5 (RBBP5)
• Synonyms: RBBP-5; Retinoblastoma-binding protein RBQ-3
• Gene Name: RBBP5
• Related Disease:
  Prostate cancer
  Prostate carcinoma
  Glioblastoma multiforme
  Glioma
  Neoplasm
  Plasma cell myeloma
  Hepatocellular carcinoma
• UniProt ID: RBBP5_HUMAN
• PDB ID: 3P4F; 4X8N; 4X8P; 5F6K; 5F6L; 6KIU; 6KIV; 6KIW; 6KIX; 6KIZ; 6KM7; 6PWV; 6PWW; 6PWX; 6W5I; 6W5M; 6W5N; 7BRE; 7MBM; 7MBN; 7UD5; 7W67; 7W6A; 7W6I; 7W6J; 7W6L; 8DU4
• Pfam ID: PF00400
• Sequence:
  MNLELLESFGQNYPEEADGTLDCISMALTCTFNRWGTLLAVGCNDGRIVIWDFLTRGIAK
  IISAHIHPVCSLCWSRDGHKLVSASTDNIVSQWDVLSGDCDQRFRFPSPILKVQYHPRDQ
  NKVLVCPMKSAPVMLTLSDSKHVVLPVDDDSDLNVVASFDRRGEYIYTGNAKGKILVLKT
  DSQDLVASFRVTTGTSNTTAIKSIEFARKGSCFLINTADRIIRVYDGREILTCGRDGEPE
  PMQKLQDLVNRTPWKKCCFSGDGEYIVAGSARQHALYIWEKSIGNLVKILHGTRGELLLD
  VAWHPVRPIIASISSGVVSIWAQNQVENWSAFAPDFKELDENVEYEERESEFDIEDEDKS
  EPEQTGADAAEDEEVDVTSVDPIAAFCSSDEELEDSKALLYLPIAPEVEDPEENPYGPPP
  DAVQTSLMDEGASSEKKRQSSADGSQPPKKKPKTTNIELQGVPNDEVHPLLGVKGDGKSK
  KKQAGRPKGSKGKEKDSPFKPKLYKGDRGLPLEGSAKGKVQAELSQPLTAGGAISELL
• Function: In embryonic stem (ES) cells, plays a crucial role in the differentiation potential, particularly along the neural lineage, regulating gene induction and H3 'Lys-4' methylation at key developmental loci, including that mediated by retinoic acid. Does not affect ES cell self-renewal. Component or associated component of some histone methyltransferase complexes which regulates transcription through recruitment of those complexes to gene promoters. As part of the MLL1/MLL complex, involved in mono-, di- and trimethylation at 'Lys-4' of histone H3. Histone H3 'Lys-4' methylation represents a specific tag for epigenetic transcriptional activation. In association with ASH2L and WDR5, stimulates the histone methyltransferase activities of KMT2A, KMT2B, KMT2C, KMT2D, SETD1A and SETD1B.
• Tissue Specificity: Ubiquitously expressed.
• KEGG Pathway: Cushing syndrome (hsa04934)
• Reactome Pathway:
  PKMTs methylate histone lysines (R-HSA-3214841)
  Deactivation of the beta-catenin transactivating complex (R-HSA-3769402)
  Activation of anterior HOX genes in hindbrain development during early embryogenesis (R-HSA-5617472)
  RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function (R-HSA-8936459)
  Neddylation (R-HSA-8951664)
  Formation of WDR5-containing histone-modifying complexes (R-HSA-9772755)
  Formation of the beta-catenin (R-HSA-201722)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Prostate cancer	DISF190Y	Definitive	Biomarker	[1]
Prostate carcinoma	DISMJPLE	Definitive	Biomarker	[1]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[2]
Glioma	DIS5RPEH	Strong	Altered Expression	[3]
Neoplasm	DISZKGEW	Strong	Altered Expression	[4]
Plasma cell myeloma	DIS0DFZ0	Strong	Biomarker	[5]
Hepatocellular carcinoma	DIS0J828	Limited	Altered Expression	[4]

14 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 Retinoblastoma-binding protein 5 (RBBP5).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Retinoblastoma-binding protein 5 (RBBP5).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Retinoblastoma-binding protein 5 (RBBP5).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Retinoblastoma-binding protein 5 (RBBP5).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Retinoblastoma-binding protein 5 (RBBP5).	[10]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Retinoblastoma-binding protein 5 (RBBP5).	[11]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of Retinoblastoma-binding protein 5 (RBBP5).	[12]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Retinoblastoma-binding protein 5 (RBBP5).	[13]
Menthol	DMG2KW7	Approved	Menthol decreases the expression of Retinoblastoma-binding protein 5 (RBBP5).	[14]
Amphotericin B	DMTAJQE	Approved	Amphotericin B decreases the expression of Retinoblastoma-binding protein 5 (RBBP5).	[15]
Daunorubicin	DMQUSBT	Approved	Daunorubicin affects the expression of Retinoblastoma-binding protein 5 (RBBP5).	[16]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Retinoblastoma-binding protein 5 (RBBP5).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Retinoblastoma-binding protein 5 (RBBP5).	[19]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Retinoblastoma-binding protein 5 (RBBP5).	[21]

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 Retinoblastoma-binding protein 5 (RBBP5).	[18]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Retinoblastoma-binding protein 5 (RBBP5).	[20]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Retinoblastoma-binding protein 5 (RBBP5).	[20]

References

• [1] Role of RbBP5 and H3K4me3 in the vicinity of Snail transcription start site during epithelial-mesenchymal transition in prostate cancer cell.Oncotarget. 2016 Oct 4;7(40):65553-65567. doi: 10.18632/oncotarget.11549.
• [2] Integrated genomic profiling identifies candidate genes implicated in glioma-genesis and a novel LEO1-SLC12A1 fusion gene.Genes Chromosomes Cancer. 2010 Jun;49(6):509-17. doi: 10.1002/gcc.20760.
• [3] Expression and clinical role of RBQ3 in gliomas.J Neurol Sci. 2015 Dec 15;359(1-2):177-84. doi: 10.1016/j.jns.2015.10.058. Epub 2015 Nov 9.
• [4] Retinoblastoma Binding Protein 5 Correlates with the Progression in Hepatocellular Carcinoma.Biomed Res Int. 2018 Nov 7;2018:1073432. doi: 10.1155/2018/1073432. eCollection 2018.
• [5] RBQ3 participates in multiple myeloma cell proliferation, adhesion and chemoresistance.Int J Biol Macromol. 2016 Oct;91:115-22. doi: 10.1016/j.ijbiomac.2016.05.050. Epub 2016 May 14.
• [6] 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.
• [7] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [8] 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.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] 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.
• [11] Alcohol triggered bile acid disequilibrium by suppressing BSEP to sustain hepatocellular carcinoma progression. Chem Biol Interact. 2022 Apr 1;356:109847. doi: 10.1016/j.cbi.2022.109847. Epub 2022 Feb 9.
• [12] In vitro and in vivo irinotecan-induced changes in expression profiles of cell cycle and apoptosis-associated genes in acute myeloid leukemia cells. Mol Cancer Ther. 2005 Jun;4(6):885-900.
• [13] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [14] Repurposing L-menthol for systems medicine and cancer therapeutics? L-menthol induces apoptosis through caspase 10 and by suppressing HSP90. OMICS. 2016 Jan;20(1):53-64.
• [15] Differential expression of microRNAs and their predicted targets in renal cells exposed to amphotericin B and its complex with copper (II) ions. Toxicol Mech Methods. 2017 Sep;27(7):537-543. doi: 10.1080/15376516.2017.1333554. Epub 2017 Jun 8.
• [16] Daunorubicin-induced variations in gene transcription: commitment to proliferation arrest, senescence and apoptosis. Biochem J. 2003 Jun 15;372(Pt 3):703-11. doi: 10.1042/BJ20021950.
• [17] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [18] 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.
• [19] 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.
• [20] 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.
• [21] 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.