Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTD19VO6)

• DOT Name: Methyl-CpG-binding domain protein 1 (MBD1)
• Synonyms: CXXC-type zinc finger protein 3; Methyl-CpG-binding protein MBD1; Protein containing methyl-CpG-binding domain 1
• Gene Name: MBD1
• Related Disease:
  Rett syndrome
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Carcinoma
  Influenza
  Lung cancer
  Lung carcinoma
  Lung neoplasm
  Neoplasm
  Neuralgia
  Pancreatic cancer
  Pancreatic tumour
  Plasma cell myeloma
  Plasma cell neoplasm
  Prostate neoplasm
  Scleroderma
  Subacute cutaneous lupus erythematosus
  Systemic sclerosis
  Thyroid tumor
  Vitiligo
  Wilson disease
  Adenocarcinoma
  Gallbladder cancer
  Gallbladder carcinoma
  Glioma
  Leiomyosarcoma
  Prostate cancer
  Prostate carcinoma
• UniProt ID: MBD1_HUMAN
• PDB ID: 1D9N; 1IG4; 4D4W; 5W9Q; 6D1T
• Pfam ID: PF01429 ; PF02008
• Sequence:
  MAEDWLDCPALGPGWKRREVFRKSGATCGRSDTYYQSPTGDRIRSKVELTRYLGPACDLT
  LFDFKQGILCYPAPKAHPVAVASKKRKKPSRPAKTRKRQVGPQSGEVRKEAPRDETKADT
  DTAPASFPAPGCCENCGISFSGDGTQRQRLKTLCKDCRAQRIAFNREQRMFKRVGCGECA
  ACQVTEDCGACSTCLLQLPHDVASGLFCKCERRRCLRIVERSRGCGVCRGCQTQEDCGHC
  PICLRPPRPGLRRQWKCVQRRCLRGKHARRKGGCDSKMAARRRPGAQPLPPPPPSQSPEP
  TEPHPRALAPSPPAEFIYYCVDEDELQPYTNRRQNRKCGACAACLRRMDCGRCDFCCDKP
  KFGGSNQKRQKCRWRQCLQFAMKRLLPSVWSESEDGAGSPPPYRRRKRPSSARRHHLGPT
  LKPTLATRTAQPDHTQAPTKQEAGGGFVLPPPGTDLVFLREGASSPVQVPGPVAASTEAL
  LQEAQCSGLSWVVALPQVKQEKADTQDEWTPGTAVLTSPVLVPGCPSKAVDPGLPSVKQE
  PPDPEEDKEENKDDSASKLAPEEEAGGAGTPVITEIFSLGGTRFRDTAVWLPRSKDLKKP
  GARKQ
• Function: Transcriptional repressor that binds CpG islands in promoters where the DNA is methylated at position 5 of cytosine within CpG dinucleotides. Binding is abolished by the presence of 7-mG that is produced by DNA damage by methylmethanesulfonate (MMS). Acts as transcriptional repressor and plays a role in gene silencing by recruiting ATF7IP, which in turn recruits factors such as the histone methyltransferase SETDB1. Probably forms a complex with SETDB1 and ATF7IP that represses transcription and couples DNA methylation and histone 'Lys-9' trimethylation. Isoform 1 and isoform 2 can also repress transcription from unmethylated promoters.
• Tissue Specificity: Widely expressed.
• Reactome Pathway: SUMOylation of transcription cofactors (R-HSA-3899300)

Molecular Interaction Atlas (MIA) of This DOT

29 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Rett syndrome	DISGG5UV	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[2]
Breast cancer	DIS7DPX1	Strong	Genetic Variation	[3]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[3]
Carcinoma	DISH9F1N	Strong	Altered Expression	[4]
Influenza	DIS3PNU3	Strong	Biomarker	[5]
Lung cancer	DISCM4YA	Strong	Genetic Variation	[6]
Lung carcinoma	DISTR26C	Strong	Genetic Variation	[6]
Lung neoplasm	DISVARNB	Strong	Genetic Variation	[6]
Neoplasm	DISZKGEW	Strong	Biomarker	[7]
Neuralgia	DISWO58J	Strong	Biomarker	[8]
Pancreatic cancer	DISJC981	Strong	Biomarker	[9]
Pancreatic tumour	DIS3U0LK	Strong	Biomarker	[4]
Plasma cell myeloma	DIS0DFZ0	Strong	Genetic Variation	[10]
Plasma cell neoplasm	DIS2PJJM	Strong	Genetic Variation	[10]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[11]
Scleroderma	DISVQ342	Strong	Biomarker	[12]
Subacute cutaneous lupus erythematosus	DIS6XDK0	Strong	Altered Expression	[13]
Systemic sclerosis	DISF44L6	Strong	Biomarker	[12]
Thyroid tumor	DISLVKMD	Strong	Biomarker	[14]
Vitiligo	DISR05SL	Strong	Biomarker	[15]
Wilson disease	DISVS9H7	Strong	Biomarker	[16]
Adenocarcinoma	DIS3IHTY	moderate	Genetic Variation	[17]
Gallbladder cancer	DISXJUAF	Disputed	Altered Expression	[18]
Gallbladder carcinoma	DISD6ACL	Disputed	Altered Expression	[18]
Glioma	DIS5RPEH	Limited	Altered Expression	[19]
Leiomyosarcoma	DIS6COXM	Limited	Biomarker	[20]
Prostate cancer	DISF190Y	Limited	Biomarker	[11]
Prostate carcinoma	DISMJPLE	Limited	Altered Expression	[21]

4 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 1 (MBD1).	[22]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Methyl-CpG-binding domain protein 1 (MBD1).	[31]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Methyl-CpG-binding domain protein 1 (MBD1).	[32]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Methyl-CpG-binding domain protein 1 (MBD1).	[32]

10 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 Methyl-CpG-binding domain protein 1 (MBD1).	[23]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Methyl-CpG-binding domain protein 1 (MBD1).	[24]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Methyl-CpG-binding domain protein 1 (MBD1).	[25]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Methyl-CpG-binding domain protein 1 (MBD1).	[26]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Methyl-CpG-binding domain protein 1 (MBD1).	[27]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Methyl-CpG-binding domain protein 1 (MBD1).	[28]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Methyl-CpG-binding domain protein 1 (MBD1).	[29]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Methyl-CpG-binding domain protein 1 (MBD1).	[30]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Methyl-CpG-binding domain protein 1 (MBD1).	[28]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of Methyl-CpG-binding domain protein 1 (MBD1).	[33]

References

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• [2] Methyl-CpG-DNA binding proteins in human prostate cancer: expression of CXXC sequence containing MBD1 and repression of MBD2 and MeCP2.Biochem Biophys Res Commun. 2003 Mar 21;302(4):759-66. doi: 10.1016/s0006-291x(03)00253-5.
• [3] A candidate CpG SNP approach identifies a breast cancer associated ESR1-SNP.Int J Cancer. 2011 Oct 1;129(7):1689-98. doi: 10.1002/ijc.25786. Epub 2011 Mar 11.
• [4] Proteomic analysis of differential proteins in pancreatic carcinomas: Effects of MBD1 knock-down by stable RNA interference.BMC Cancer. 2008 Apr 29;8:121. doi: 10.1186/1471-2407-8-121.
• [5] Expression of mouse beta-defensin-3 in MDCK cells and its anti-influenza-virus activity.Arch Virol. 2009;154(4):639-47. doi: 10.1007/s00705-009-0352-6. Epub 2009 Mar 20.
• [6] Methyl-CpG binding domain 1 gene polymorphisms and lung cancer risk in a Chinese population.Biomarkers. 2008 Sep;13(6):607-17. doi: 10.1080/13547500802168031.
• [7] Up-regulation of MBD1 promotes pancreatic cancer cell epithelial-mesenchymal transition and invasion by epigenetic down-regulation of E-cadherin.Curr Mol Med. 2013 Mar;13(3):387-400.
• [8] MBD1 Contributes to the Genesis of Acute Pain and Neuropathic Pain by Epigenetic Silencing of Oprm1 and Kcna2 Genes in Primary Sensory Neurons.J Neurosci. 2018 Nov 14;38(46):9883-9899. doi: 10.1523/JNEUROSCI.0880-18.2018. Epub 2018 Sep 28.
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• [10] Biphenotypic plasma cell myeloma: two cases of plasma cell neoplasm with a coexpression of kappa and lambda light chains.Int J Clin Exp Pathol. 2015 Jul 1;8(7):8536-44. eCollection 2015.
• [11] The long tail of oncogenic drivers in prostate cancer.Nat Genet. 2018 May;50(5):645-651. doi: 10.1038/s41588-018-0078-z. Epub 2018 Apr 2.
• [12] Localization of autoepitopes on the PCM-1 autoantigen using scleroderma sera with autoantibodies against the centrosome.Mol Biol Rep. 1998 Mar;25(2):111-9. doi: 10.1023/a:1006814217037.
• [13] 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.
• [14] RET/PTC fusion gene rearrangements in Japanese thyroid carcinomas.Eur Arch Otorhinolaryngol. 2005 May;262(5):368-73. doi: 10.1007/s00405-004-0835-8. Epub 2004 Sep 11.
• [15] 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.
• [16] Copper relay path through the N-terminus of Wilson disease protein, ATP7B.Metallomics. 2019 Sep 1;11(9):1472-1480. doi: 10.1039/c9mt00147f. Epub 2019 Jul 19.
• [17] Methyl-CpG binding domain 1 gene polymorphisms and risk of primary lung cancer.Cancer Epidemiol Biomarkers Prev. 2005 Nov;14(11 Pt 1):2474-80. doi: 10.1158/1055-9965.EPI-05-0423.
• [18] MBD1 promotes the malignant behavior of gallbladder cancer cells and induces chemotherapeutic resistance to gemcitabine.Cancer Cell Int. 2019 Sep 9;19:232. doi: 10.1186/s12935-019-0948-1. eCollection 2019.
• [19] Overexpression of RFT induces G1-S arrest and apoptosis via p53/p21(Waf1) pathway in glioma cell.Biochem Biophys Res Commun. 2004 May 7;317(3):902-8. doi: 10.1016/j.bbrc.2004.03.120.
• [20] Discovery and mechanisms of host defense to oncogenesis: targeting the -defensin-1 peptide as a natural tumor inhibitor.Cancer Biol Ther. 2019;20(6):774-786. doi: 10.1080/15384047.2018.1564564. Epub 2019 Mar 22.
• [21] Silencing of MBD1 and MeCP2 in prostate-cancer-derived PC3 cells produces differential gene expression profiles and cellular phenotypes.Biosci Rep. 2008 Dec;28(6):319-26. doi: 10.1042/BSR20080032.
• [22] 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.
• [23] 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.
• [24] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [25] Effects of chronic exposure to arsenic and estrogen on epigenetic regulatory genes expression and epigenetic code in human prostate epithelial cells. PLoS One. 2012;7(8):e43880. doi: 10.1371/journal.pone.0043880. Epub 2012 Aug 27.
• [26] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
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• [28] 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.
• [29] 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.
• [30] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [31] 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.
• [32] 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.
• [33] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.