Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0D0JVD)

• DOT Name: Mediator of RNA polymerase II transcription subunit 15 (MED15)
• Synonyms: Activator-recruited cofactor 105 kDa component; ARC105; CTG repeat protein 7a; Mediator complex subunit 15; Positive cofactor 2 glutamine/Q-rich-associated protein; PC2 glutamine/Q-rich-associated protein; TPA-inducible gene 1 protein; TIG-1; Trinucleotide repeat-containing gene 7 protein
• Gene Name: MED15
• Related Disease:
  Advanced cancer
  Benign prostatic hyperplasia
  Bladder cancer
  Cardiovascular disease
  Clear cell renal carcinoma
  Colon cancer
  Colon carcinoma
  DiGeorge syndrome
  Endometrial carcinoma
  Esophageal squamous cell carcinoma
  Familial adenomatous polyposis
  Gastric cancer
  Hepatocellular carcinoma
  Inflammatory breast cancer
  leukaemia
  Leukemia
  Nasopharyngeal carcinoma
  Oral cancer
  Oropharyngeal cancer
  Oropharyngeal carcinoma
  Prostate neoplasm
  Psoriasis
  Renal cell carcinoma
  Stomach cancer
  Urinary bladder cancer
  Urinary bladder neoplasm
  Velocardiofacial syndrome
  Carcinoma
  Epstein barr virus infection
  Schizoaffective disorder
  Benign neoplasm
  Carcinoma of liver and intrahepatic biliary tract
  Castration-resistant prostate carcinoma
  Head-neck squamous cell carcinoma
  Liver cancer
  Prostate cancer
  Prostate carcinoma
• UniProt ID: MED15_HUMAN
• PDB ID: 2GUT; 7EMF; 7ENA; 7ENC; 7ENJ; 7LBM; 8GXQ; 8GXS
• Pfam ID: PF09606 ; PF21539 ; PF21538
• Sequence:
  MDVSGQETDWRSTAFRQKLVSQIEDAMRKAGVAHSKSSKDMESHVFLKAKTRDEYLSLVA
  RLIIHFRDIHNKKSQASVSDPMNALQSLTGGPAAGAAGIGMPPRGPGQSLGGMGSLGAMG
  QPMSLSGQPPPGTSGMAPHSMAVVSTATPQTQLQLQQVALQQQQQQQQFQQQQQAALQQQ
  QQQQQQQQFQAQQSAMQQQFQAVVQQQQQLQQQQQQQQHLIKLHHQNQQQIQQQQQQLQR
  IAQLQLQQQQQQQQQQQQQQQQALQAQPPIQQPPMQQPQPPPSQALPQQLQQMHHTQHHQ
  PPPQPQQPPVAQNQPSQLPPQSQTQPLVSQAQALPGQMLYTQPPLKFVRAPMVVQQPPVQ
  PQVQQQQTAVQTAQAAQMVAPGVQMITEALAQGGMHIRARFPPTTAVSAIPSSSIPLGRQ
  PMAQVSQSSLPMLSSPSPGQQVQTPQSMPPPPQPSPQPGQPSSQPNSNVSSGPAPSPSSF
  LPSPSPQPSQSPVTARTPQNFSVPSPGPLNTPVNPSSVMSPAGSSQAEEQQYLDKLKQLS
  KYIEPLRRMINKIDKNEDRKKDLSKMKSLLDILTDPSKRCPLKTLQKCEIALEKLKNDMA
  VPTPPPPPVPPTKQQYLCQPLLDAVLANIRSPVFNHSLYRTFVPAMTAIHGPPITAPVVC
  TRKRRLEDDERQSIPSVLQGEVARLDPKFLVNLDPSHCSNNGTVHLICKLDDKDLPSVPP
  LELSVPADYPAQSPLWIDRQWQYDANPFLQSVHRCMTSRLLQLPDKHSVTALLNTWAQSV
  HQACLSAA
• Function: Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors. Required for cholesterol-dependent gene regulation. Positively regulates the Nodal signaling pathway.
• Tissue Specificity: Expressed in all tissues examined, including heart, brain, lung, spleen, thymus, pancreas, blood leukocyte and placenta. However, the level of expression varied, with highest expression in the placenta and peripheral blood and lowest in the pancreas and kidney.
• Reactome Pathway:
  Generic Transcription Pathway (R-HSA-212436)
  Transcriptional regulation of white adipocyte differentiation (R-HSA-381340)
  PPARA activates gene expression (R-HSA-1989781)

Molecular Interaction Atlas (MIA) of This DOT

37 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Benign prostatic hyperplasia	DISI3CW2	Strong	Altered Expression	[2]
Bladder cancer	DISUHNM0	Strong	Biomarker	[3]
Cardiovascular disease	DIS2IQDX	Strong	Biomarker	[4]
Clear cell renal carcinoma	DISBXRFJ	Strong	Genetic Variation	[5]
Colon cancer	DISVC52G	Strong	Biomarker	[6]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[6]
DiGeorge syndrome	DIST1RKO	Strong	Biomarker	[7]
Endometrial carcinoma	DISXR5CY	Strong	Biomarker	[8]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Posttranslational Modification	[9]
Familial adenomatous polyposis	DISW53RE	Strong	Biomarker	[10]
Gastric cancer	DISXGOUK	Strong	Biomarker	[11]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[1]
Inflammatory breast cancer	DIS3QRWA	Strong	Biomarker	[12]
leukaemia	DISS7D1V	Strong	Posttranslational Modification	[13]
Leukemia	DISNAKFL	Strong	Posttranslational Modification	[13]
Nasopharyngeal carcinoma	DISAOTQ0	Strong	Posttranslational Modification	[14]
Oral cancer	DISLD42D	Strong	Biomarker	[15]
Oropharyngeal cancer	DISDAMTJ	Strong	Biomarker	[15]
Oropharyngeal carcinoma	DIS7K3AI	Strong	Biomarker	[15]
Prostate neoplasm	DISHDKGQ	Strong	Posttranslational Modification	[16]
Psoriasis	DIS59VMN	Strong	Altered Expression	[17]
Renal cell carcinoma	DISQZ2X8	Strong	Genetic Variation	[5]
Stomach cancer	DISKIJSX	Strong	Genetic Variation	[18]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[3]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[3]
Velocardiofacial syndrome	DISOSBTY	Strong	Biomarker	[19]
Carcinoma	DISH9F1N	moderate	Altered Expression	[18]
Epstein barr virus infection	DISOO0WT	moderate	Biomarker	[14]
Schizoaffective disorder	DISLBW6B	moderate	Biomarker	[20]
Benign neoplasm	DISDUXAD	Limited	Altered Expression	[21]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Limited	Altered Expression	[1]
Castration-resistant prostate carcinoma	DISVGAE6	Limited	Altered Expression	[22]
Head-neck squamous cell carcinoma	DISF7P24	Limited	Biomarker	[21]
Liver cancer	DISDE4BI	Limited	Altered Expression	[1]
Prostate cancer	DISF190Y	Limited	Altered Expression	[23]
Prostate carcinoma	DISMJPLE	Limited	Altered Expression	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	Mediator of RNA polymerase II transcription subunit 15 (MED15) affects the response to substance of Methotrexate.	[33]

8 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 Mediator of RNA polymerase II transcription subunit 15 (MED15).	[24]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Mediator of RNA polymerase II transcription subunit 15 (MED15).	[25]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Mediator of RNA polymerase II transcription subunit 15 (MED15).	[26]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Mediator of RNA polymerase II transcription subunit 15 (MED15).	[27]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Mediator of RNA polymerase II transcription subunit 15 (MED15).	[28]
Selenium	DM25CGV	Approved	Selenium increases the expression of Mediator of RNA polymerase II transcription subunit 15 (MED15).	[29]
Sulindac	DM2QHZU	Approved	Sulindac increases the expression of Mediator of RNA polymerase II transcription subunit 15 (MED15).	[30]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Mediator of RNA polymerase II transcription subunit 15 (MED15).	[29]

2 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 decreases the methylation of Mediator of RNA polymerase II transcription subunit 15 (MED15).	[31]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Mediator of RNA polymerase II transcription subunit 15 (MED15).	[32]

References

• [1] Increased mediator complex subunit 15 expression is associated with poor prognosis in hepatocellular carcinoma.Oncol Lett. 2018 Apr;15(4):4303-4313. doi: 10.3892/ol.2018.7820. Epub 2018 Jan 18.
• [2] Absolute quantitation of DNA methylation of 28 candidate genes in prostate cancer using pyrosequencing.Dis Markers. 2011;30(4):151-61. doi: 10.3233/DMA-2011-0790.
• [3] The knockdown of the Mediator complex subunit MED15 restrains urothelial bladder cancer cells' malignancy.Oncol Lett. 2018 Sep;16(3):3013-3021. doi: 10.3892/ol.2018.9014. Epub 2018 Jun 25.
• [4] Mediating lipid biosynthesis: implications for cardiovascular disease.Trends Cardiovasc Med. 2013 Oct;23(7):269-73. doi: 10.1016/j.tcm.2013.03.002. Epub 2013 Apr 4.
• [5] A Rare Partner of TFE3 in the Xp11 Translocation Renal Cell Carcinoma: Clinicopathological Analyses and Detection of MED15-TFE3 Fusion.Biomed Res Int. 2019 Nov 11;2019:5974089. doi: 10.1155/2019/5974089. eCollection 2019.
• [6] G protein-coupled receptor kinase 5 mediates Tazarotene-induced gene 1-induced growth suppression of human colon cancer cells.BMC Cancer. 2011 May 17;11:175. doi: 10.1186/1471-2407-11-175.
• [7] Isolation and characterization of a novel gene from the DiGeorge chromosomal region that encodes for a mediator subunit.Genomics. 2001 Jun 15;74(3):320-32. doi: 10.1006/geno.2001.6566.
• [8] Discovery of epigenetically masked tumor suppressor genes in endometrial cancer.Mol Cancer Res. 2005 May;3(5):261-9. doi: 10.1158/1541-7786.MCR-04-0110.
• [9] DNA methylation of genes linked to retinoid signaling in squamous cell carcinoma of the esophagus: DNA methylation of CRBP1 and TIG1 is associated with tumor stage.Cancer Sci. 2005 Sep;96(9):571-7. doi: 10.1111/j.1349-7006.2005.00082.x.
• [10] Optimal use of a panel of methylation markers with GSTP1 hypermethylation in the diagnosis of prostate adenocarcinoma.Clin Cancer Res. 2004 Aug 15;10(16):5518-22. doi: 10.1158/1078-0432.CCR-04-0108.
• [11] Quantitative assessment of gene methylation in neoplastic and non-neoplastic gastric epithelia using methylation-specific DNA microarray.Pathol Int. 2009 Dec;59(12):895-9. doi: 10.1111/j.1440-1827.2009.02458.x.
• [12] TIG1 promotes the development and progression of inflammatory breast cancer through activation of Axl kinase.Cancer Res. 2013 Nov 1;73(21):6516-25. doi: 10.1158/0008-5472.CAN-13-0967. Epub 2013 Sep 6.
• [13] Hypermethylation and silencing of the putative tumor suppressor Tazarotene-induced gene 1 in human cancers.Cancer Res. 2004 Apr 1;64(7):2411-7. doi: 10.1158/0008-5472.can-03-0164.
• [14] Role of the RARRES1 gene in nasopharyngeal carcinoma.Cancer Genet Cytogenet. 2009 Oct;194(1):58-64. doi: 10.1016/j.cancergencyto.2009.06.005.
• [15] Promoter Hypermethylation of Tumor-Suppressor Genes p16(INK4a),RASSF1A,TIMP3, and PCQAP/MED15 in Salivary DNA as a Quadruple Biomarker Panel for Early Detection of Oral and Oropharyngeal Cancers.Biomolecules. 2019 Apr 12;9(4):148. doi: 10.3390/biom9040148.
• [16] Methylation of the retinoid response gene TIG1 in prostate cancer correlates with methylation of the retinoic acid receptor beta gene.Oncogene. 2004 Mar 18;23(12):2241-9. doi: 10.1038/sj.onc.1207328.
• [17] Tazarotene-induced gene 1 (TIG1), a novel retinoic acid receptor-responsive gene in skin.J Invest Dermatol. 1996 Feb;106(2):269-74. doi: 10.1111/1523-1747.ep12340668.
• [18] Expression and mutation analysis of TIG1 (tazarotene-induced gene 1) in human gastric cancer.Oncol Res. 2009;17(11-12):571-80. doi: 10.3727/096504009789745584.
• [19] An atypical 0.8 Mb inherited duplication of 22q11.2 associated with psychomotor impairment.Eur J Med Genet. 2012 Nov;55(11):650-5. doi: 10.1016/j.ejmg.2012.06.014. Epub 2012 Jul 14.
• [20] Association study between CAG trinucleotide repeats in the PCQAP gene (PC2 glutamine/Q-rich-associated protein) and schizophrenia.Am J Med Genet B Neuropsychiatr Genet. 2003 Jan 1;116B(1):32-5. doi: 10.1002/ajmg.b.10008.
• [21] Clinical and molecular implications of MED15 in head and neck squamous cell carcinoma.Am J Pathol. 2015 Apr;185(4):1114-22. doi: 10.1016/j.ajpath.2014.12.010. Epub 2015 Mar 16.
• [22] MED15, encoding a subunit of the mediator complex, is overexpressed at high frequency in castration-resistant prostate cancer.Int J Cancer. 2014 Jul 1;135(1):19-26. doi: 10.1002/ijc.28647. Epub 2013 Dec 9.
• [23] MED15 overexpression in prostate cancer arises during androgen deprivation therapy via PI3K/mTOR signaling.Oncotarget. 2017 Jan 31;8(5):7964-7976. doi: 10.18632/oncotarget.13860.
• [24] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [25] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [26] 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.
• [27] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [28] 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.
• [29] 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.
• [30] Expression profile analysis of colon cancer cells in response to sulindac or aspirin. Biochem Biophys Res Commun. 2002 Mar 29;292(2):498-512.
• [31] 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.
• [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 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.