Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTRL76H5)

• DOT Name: Methyl-CpG-binding domain protein 3 (MBD3)
• Synonyms: Methyl-CpG-binding protein MBD3
• Gene Name: MBD3
• Related Disease:
  Acute myelogenous leukaemia
  Advanced cancer
  Autism
  leukaemia
  Leukemia
  Lung cancer
  Lung carcinoma
  Malignant glioma
  Promyelocytic leukaemia
  Silver-Russell syndrome
  Subacute cutaneous lupus erythematosus
  Vitiligo
  Gastritis
  Neoplasm
  Pancreatic cancer
  Pemphigus vulgaris
  Carcinoma of liver and intrahepatic biliary tract
  Liver cancer
  Non-small-cell lung cancer
• UniProt ID: MBD3_HUMAN
• PDB ID: 2MB7; 6CC8; 6CCG; 6CEU; 6CEV
• Pfam ID: PF01429 ; PF14048 ; PF16564
• Sequence:
  MERKRWECPALPQGWEREEVPRRSGLSAGHRDVFYYSPSGKKFRSKPQLARYLGGSMDLS
  TFDFRTGKMLMSKMNKSRQRVRYDSSNQVKGKPDLNTALPVRQTASIFKQPVTKITNHPS
  NKVKSDPQKAVDQPRQLFWEKKLSGLNAFDIAEELVKTMDLPKGLQGVGPGCTDETLLSA
  IASALHTSTMPITGQLSAAVEKNPGVWLNTTQPLCKAFMVTDEDIRKQEELVQQVRKRLE
  EALMADMLAHVEELARDGEAPLDKACAEDDDEEDEEEEEEEPDPDPEMEHV
• Function: Acts as a component of the histone deacetylase NuRD complex which participates in the remodeling of chromatin. Acts as transcriptional repressor and plays a role in gene silencing. Does not bind to methylated DNA by itself. Binds to a lesser degree DNA containing unmethylated CpG dinucleotides. Recruits histone deacetylases and DNA methyltransferases.
• KEGG Pathway: ATP-dependent chromatin remodeling (hsa03082)
• Reactome Pathway:
  ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression (R-HSA-427389)
  Regulation of TP53 Activity through Acetylation (R-HSA-6804758)
  RNA Polymerase I Transcription Initiation (R-HSA-73762)
  Regulation of PTEN gene transcription (R-HSA-8943724)
  Potential therapeutics for SARS (R-HSA-9679191)
  HDACs deacetylate histones (R-HSA-3214815)

Molecular Interaction Atlas (MIA) of This DOT

19 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	Altered Expression	[1]
Autism	DISV4V1Z	Strong	Biomarker	[2]
leukaemia	DISS7D1V	Strong	Biomarker	[1]
Leukemia	DISNAKFL	Strong	Biomarker	[1]
Lung cancer	DISCM4YA	Strong	Biomarker	[3]
Lung carcinoma	DISTR26C	Strong	Biomarker	[3]
Malignant glioma	DISFXKOV	Strong	Biomarker	[4]
Promyelocytic leukaemia	DISYGG13	Strong	Posttranslational Modification	[5]
Silver-Russell syndrome	DISSVJ1D	Strong	Genetic Variation	[6]
Subacute cutaneous lupus erythematosus	DIS6XDK0	Strong	Altered Expression	[7]
Vitiligo	DISR05SL	Strong	Biomarker	[8]
Gastritis	DIS8G07K	moderate	Altered Expression	[9]
Neoplasm	DISZKGEW	moderate	Posttranslational Modification	[9]
Pancreatic cancer	DISJC981	moderate	Biomarker	[10]
Pemphigus vulgaris	DISENR62	moderate	Altered Expression	[11]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Limited	Biomarker	[12]
Liver cancer	DISDE4BI	Limited	Biomarker	[12]
Non-small-cell lung cancer	DIS5Y6R9	Limited	Altered Expression	[13]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	Methyl-CpG-binding domain protein 3 (MBD3) affects the response to substance of Methotrexate.	[27]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Methyl-CpG-binding domain protein 3 (MBD3).	[14]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Methyl-CpG-binding domain protein 3 (MBD3).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Methyl-CpG-binding domain protein 3 (MBD3).	[15]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Methyl-CpG-binding domain protein 3 (MBD3).	[16]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Methyl-CpG-binding domain protein 3 (MBD3).	[17]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Methyl-CpG-binding domain protein 3 (MBD3).	[18]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Methyl-CpG-binding domain protein 3 (MBD3).	[19]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Methyl-CpG-binding domain protein 3 (MBD3).	[20]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Methyl-CpG-binding domain protein 3 (MBD3).	[21]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Methyl-CpG-binding domain protein 3 (MBD3).	[22]
Selenium	DM25CGV	Approved	Selenium increases the expression of Methyl-CpG-binding domain protein 3 (MBD3).	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Methyl-CpG-binding domain protein 3 (MBD3).	[25]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Methyl-CpG-binding domain protein 3 (MBD3).	[26]

References

• [1] MBD3/NuRD loss participates with KDM6A program to promote DOCK5/8 expression and Rac GTPase activation in human acute myeloid leukemia.FASEB J. 2019 Apr;33(4):5268-5286. doi: 10.1096/fj.201801035R. Epub 2019 Jan 22.
• [2] Novel variants identified in methyl-CpG-binding domain genes in autistic individuals.Neurogenetics. 2010 Jul;11(3):291-303. doi: 10.1007/s10048-009-0228-7. Epub 2009 Nov 18.
• [3] Identification of a nuclear protein, LRRC42, involved in lung carcinogenesis.Int J Oncol. 2014 Jul;45(1):147-56. doi: 10.3892/ijo.2014.2418. Epub 2014 May 6.
• [4] Regulatory landscape and clinical implication of MBD3 in human malignant glioma.Oncotarget. 2016 Dec 6;7(49):81698-81714. doi: 10.18632/oncotarget.13173.
• [5] MBD3, a component of the NuRD complex, facilitates chromatin alteration and deposition of epigenetic marks.Mol Cell Biol. 2008 Oct;28(19):5912-23. doi: 10.1128/MCB.00467-08. Epub 2008 Jul 21.
• [6] MBD3 mutations are not responsible for ICR1 hypomethylation in Silver-Russell syndrome.Eur J Med Genet. 2010 Jan-Feb;53(1):23-4. doi: 10.1016/j.ejmg.2009.12.002. Epub 2009 Dec 16.
• [7] Abnormal DNA methylation in T cells from patients with subacute cutaneous lupus erythematosus.Br J Dermatol. 2008 Sep;159(4):827-33. doi: 10.1111/j.1365-2133.2008.08758.x. Epub 2008 Jul 17.
• [8] Abnormal DNA methylation in peripheral blood mononuclear cells from patients with vitiligo.Br J Dermatol. 2010 Oct;163(4):736-42. doi: 10.1111/j.1365-2133.2010.09919.x. Epub 2010 Sep 6.
• [9] Reduced mRNA expression levels of MBD2 and MBD3 in gastric carcinogenesis.Tumour Biol. 2014 Apr;35(4):3447-53. doi: 10.1007/s13277-013-1455-y. Epub 2013 Dec 13.
• [10] Methyl-CpG-binding domain 3 inhibits epithelial-mesenchymal transition in pancreatic cancer cells via TGF-/Smad signalling.Br J Cancer. 2017 Jan 3;116(1):91-99. doi: 10.1038/bjc.2016.397. Epub 2016 Nov 29.
• [11] Aberrant epigenetic modifications in peripheral blood mononuclear cells from patients with pemphigus vulgaris.Br J Dermatol. 2012 Sep;167(3):523-31. doi: 10.1111/j.1365-2133.2012.11007.x. Epub 2012 Aug 10.
• [12] MBD3 inhibits formation of liver cancer stem cells.Oncotarget. 2017 Jan 24;8(4):6067-6078. doi: 10.18632/oncotarget.13496.
• [13] The expression of DNA methyltransferases and methyl-CpG-binding proteins is not associated with the methylation status of p14(ARF), p16(INK4a) and RASSF1A in human lung cancer cell lines.Oncogene. 2002 Jul 18;21(31):4822-9. doi: 10.1038/sj.onc.1205581.
• [14] 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.
• [15] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [16] 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.
• [17] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [18] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [19] 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.
• [20] Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells. Toxicol Appl Pharmacol. 2012 Jun 1;261(2):204-16.
• [21] A genomic approach to predict synergistic combinations for breast cancer treatment. Pharmacogenomics J. 2013 Feb;13(1):94-104. doi: 10.1038/tpj.2011.48. Epub 2011 Nov 15.
• [22] Gene induction and apoptosis in human hepatocellular carci-noma cells SMMC-7721 exposed to 5-aza-2'-deoxycytidine. Chin Med J (Engl). 2007 Sep 20;120(18):1626-31.
• [23] 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.
• [24] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [25] Bisphenol A Exposure Changes the Transcriptomic and Proteomic Dynamics of Human Retinoblastoma Y79 Cells. Genes (Basel). 2021 Feb 11;12(2):264. doi: 10.3390/genes12020264.
• [26] Estrogen down regulates COMT transcription via promoter DNA methylation in human breast cancer cells. Toxicol Appl Pharmacol. 2019 Mar 15;367:12-22.
• [27] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.