Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQZ4D2X)

• DOT Name: Mediator of RNA polymerase II transcription subunit 12 (MED12)
• Synonyms: Activator-recruited cofactor 240 kDa component; ARC240; CAG repeat protein 45; Mediator complex subunit 12; OPA-containing protein; Thyroid hormone receptor-associated protein complex 230 kDa component; Trap230; Trinucleotide repeat-containing gene 11 protein
• Gene Name: MED12
• Related Disease:
  Adrenocortical carcinoma
  Colorectal carcinoma
  FG syndrome 1
  Leiomyoma
  MED12-related intellectual disability syndrome
  Neoplasm
  X-linked intellectual disability with marfanoid habitus
  Acute myelogenous leukaemia
  Alpha thalassemia-X-linked intellectual disability syndrome
  Alzheimer disease
  Autosomal dominant optic atrophy, classic form
  Blepharophimosis - intellectual disability syndrome, MKB type
  Breast cancer
  Breast carcinoma
  Cholestasis-pigmentary retinopathy-cleft palate syndrome
  Clear cell renal carcinoma
  Colon cancer
  Colon carcinoma
  Depression
  Epithelial ovarian cancer
  FG syndrome 2
  FG syndrome 4
  Gastric adenocarcinoma
  Hypothyroidism
  Intellectual disability
  Leiomyosarcoma
  Lung cancer
  Lung carcinoma
  Lung squamous cell carcinoma
  Major depressive disorder
  Non-small-cell lung cancer
  Obesity
  Pancreatic adenocarcinoma
  Prostate adenocarcinoma
  Prostate carcinoma
  Renal cell carcinoma
  Small lymphocytic lymphoma
  X-linked intellectual disability
  Breast neoplasm
  Prostate cancer
  Psychotic disorder
  FG syndrome
  Hirschsprung disease
  Hirschsprung disease, susceptibility to, 1
  Pancreatic cancer
• UniProt ID: MED12_HUMAN
• Pfam ID: PF09497 ; PF12145 ; PF12144
• Sequence:
  MAAFGILSYEHRPLKRPRLGPPDVYPQDPKQKEDELTALNVKQGFNNQPAVSGDEHGSAK
  NVSFNPAKISSNFSSIIAEKLRCNTLPDTGRRKPQVNQKDNFWLVTARSQSAINTWFTDL
  AGTKPLTQLAKKVPIFSKKEEVFGYLAKYTVPVMRAAWLIKMTCAYYAAISETKVKKRHV
  DPFMEWTQIITKYLWEQLQKMAEYYRPGPAGSGGCGSTIGPLPHDVEVAIRQWDYTEKLA
  MFMFQDGMLDRHEFLTWVLECFEKIRPGEDELLKLLLPLLLRYSGEFVQSAYLSRRLAYF
  CTRRLALQLDGVSSHSSHVISAQSTSTLPTTPAPQPPTSSTPSTPFSDLLMCPQHRPLVF
  GLSCILQTILLCCPSALVWHYSLTDSRIKTGSPLDHLPIAPSNLPMPEGNSAFTQQVRAK
  LREIEQQIKERGQAVEVRWSFDKCQEATAGFTIGRVLHTLEVLDSHSFERSDFSNSLDSL
  CNRIFGLGPSKDGHEISSDDDAVVSLLCEWAVSCKRSGRHRAMVVAKLLEKRQAEIEAER
  CGESEAADEKGSIASGSLSAPSAPIFQDVLLQFLDTQAPMLTDPRSESERVEFFNLVLLF
  CELIRHDVFSHNMYTCTLISRGDLAFGAPGPRPPSPFDDPADDPEHKEAEGSSSSKLEDP
  GLSESMDIDPSSSVLFEDMEKPDFSLFSPTMPCEGKGSPSPEKPDVEKEVKPPPKEKIEG
  TLGVLYDQPRHVQYATHFPIPQEESCSHECNQRLVVLFGVGKQRDDARHAIKKITKDILK
  VLNRKGTAETDQLAPIVPLNPGDLTFLGGEDGQKRRRNRPEAFPTAEDIFAKFQHLSHYD
  QHQVTAQVSRNVLEQITSFALGMSYHLPLVQHVQFIFDLMEYSLSISGLIDFAIQLLNEL
  SVVEAELLLKSSDLVGSYTTSLCLCIVAVLRHYHACLILNQDQMAQVFEGLCGVVKHGMN
  RSDGSSAERCILAYLYDLYTSCSHLKNKFGELFSDFCSKVKNTIYCNVEPSESNMRWAPE
  FMIDTLENPAAHTFTYTGLGKSLSENPANRYSFVCNALMHVCVGHHDPDRVNDIAILCAE
  LTGYCKSLSAEWLGVLKALCCSSNNGTCGFNDLLCNVDVSDLSFHDSLATFVAILIARQC
  LLLEDLIRCAAIPSLLNAACSEQDSEPGARLTCRILLHLFKTPQLNPCQSDGNKPTVGIR
  SSCDRHLLAASQNRIVDGAVFAVLKAVFVLGDAELKGSGFTVTGGTEELPEEEGGGGSGG
  RRQGGRNISVETASLDVYAKYVLRSICQQEWVGERCLKSLCEDSNDLQDPVLSSAQAQRL
  MQLICYPHRLLDNEDGENPQRQRIKRILQNLDQWTMRQSSLELQLMIKQTPNNEMNSLLE
  NIAKATIEVFQQSAETGSSSGSTASNMPSSSKTKPVLSSLERSGVWLVAPLIAKLPTSVQ
  GHVLKAAGEELEKGQHLGSSSRKERDRQKQKSMSLLSQQPFLSLVLTCLKGQDEQREGLL
  TSLYSQVHQIVNNWRDDQYLDDCKPKQLMHEALKLRLNLVGGMFDTVQRSTQQTTEWAML
  LLEIIISGTVDMQSNNELFTTVLDMLSVLINGTLAADMSSISQGSMEENKRAYMNLAKKL
  QKELGERQSDSLEKVRQLLPLPKQTRDVITCEPQGSLIDTKGNKIAGFDSIFKKEGLQVS
  TKQKISPWDLFEGLKPSAPLSWGWFGTVRVDRRVARGEEQQRLLLYHTHLRPRPRAYYLE
  PLPLPPEDEEPPAPTLLEPEKKAPEPPKTDKPGAAPPSTEERKKKSTKGKKRSQPATKTE
  DYGMGPGRSGPYGVTVPPDLLHHPNPGSITHLNYRQGSIGLYTQNQPLPAGGPRVDPYRP
  VRLPMQKLPTRPTYPGVLPTTMTGVMGLEPSSYKTSVYRQQQPAVPQGQRLRQQLQQSQG
  MLGQSSVHQMTPSSSYGLQTSQGYTPYVSHVGLQQHTGPAGTMVPPSYSSQPYQSTHPST
  NPTLVDPTRHLQQRPSGYVHQQAPTYGHGLTSTQRFSHQTLQQTPMISTMTPMSAQGVQA
  GVRSTAILPEQQQQQQQQQQQQQQQQQQQQQQQQQQYHIRQQQQQQILRQQQQQQQQQQQ
  QQQQQQQQQQQQQQQHQQQQQQQAAPPQPQPQSQPQFQRQGLQQTQQQQQTAALVRQLQQ
  QLSNTQPQPSTNIFGRY
• 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 pre-initiation complex with RNA polymerase II and the general transcription factors. This subunit may specifically regulate transcription of targets of the Wnt signaling pathway and SHH signaling pathway.
• Tissue Specificity: Ubiquitous.
• KEGG Pathway: Thyroid hormone sig.ling pathway (hsa04919)
• 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

45 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adrenocortical carcinoma	DISZF4HX	Definitive	Biomarker	[1]
Colorectal carcinoma	DIS5PYL0	Definitive	Biomarker	[2]
FG syndrome 1	DIS8EVE3	Definitive	X-linked recessive	[3]
Leiomyoma	DISLDDFN	Definitive	Genetic Variation	[4]
MED12-related intellectual disability syndrome	DISX8R9X	Definitive	X-linked	[5]
Neoplasm	DISZKGEW	Definitive	Genetic Variation	[4]
X-linked intellectual disability with marfanoid habitus	DISEL7RK	Definitive	X-linked	[6]
Acute myelogenous leukaemia	DISCSPTN	Strong	Genetic Variation	[7]
Alpha thalassemia-X-linked intellectual disability syndrome	DISV7OEV	Strong	Biomarker	[8]
Alzheimer disease	DISF8S70	Strong	Biomarker	[9]
Autosomal dominant optic atrophy, classic form	DISXUAV9	Strong	Biomarker	[10]
Blepharophimosis - intellectual disability syndrome, MKB type	DIS5ATZ4	Strong	X-linked	[11]
Breast cancer	DIS7DPX1	Strong	Genetic Variation	[12]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[13]
Cholestasis-pigmentary retinopathy-cleft palate syndrome	DIS9GLUF	Strong	X-linked	[14]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[15]
Colon cancer	DISVC52G	Strong	Biomarker	[16]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[16]
Depression	DIS3XJ69	Strong	Biomarker	[17]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[18]
FG syndrome 2	DISSL641	Strong	Biomarker	[3]
FG syndrome 4	DISBR29S	Strong	Biomarker	[3]
Gastric adenocarcinoma	DISWWLTC	Strong	Genetic Variation	[19]
Hypothyroidism	DISR0H6D	Strong	Genetic Variation	[20]
Intellectual disability	DISMBNXP	Strong	Biomarker	[21]
Leiomyosarcoma	DIS6COXM	Strong	Altered Expression	[22]
Lung cancer	DISCM4YA	Strong	Biomarker	[15]
Lung carcinoma	DISTR26C	Strong	Biomarker	[15]
Lung squamous cell carcinoma	DISXPIBD	Strong	Genetic Variation	[19]
Major depressive disorder	DIS4CL3X	Strong	Biomarker	[17]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Genetic Variation	[23]
Obesity	DIS47Y1K	Strong	Genetic Variation	[17]
Pancreatic adenocarcinoma	DISKHX7S	Strong	Genetic Variation	[19]
Prostate adenocarcinoma	DISBZYU8	Strong	Genetic Variation	[19]
Prostate carcinoma	DISMJPLE	Strong	Genetic Variation	[24]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[15]
Small lymphocytic lymphoma	DIS30POX	Strong	Genetic Variation	[25]
X-linked intellectual disability	DISYJBY3	Strong	Posttranslational Modification	[26]
Breast neoplasm	DISNGJLM	moderate	Genetic Variation	[27]
Prostate cancer	DISF190Y	moderate	Biomarker	[28]
Psychotic disorder	DIS4UQOT	moderate	Genetic Variation	[29]
FG syndrome	DIS2MEFU	Limited	Genetic Variation	[30]
Hirschsprung disease	DISUUSM1	Limited	Biomarker	[31]
Hirschsprung disease, susceptibility to, 1	DISDU2S6	Limited	Biomarker	[31]
Pancreatic cancer	DISJC981	Limited	Biomarker	[32]

5 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 Mediator of RNA polymerase II transcription subunit 12 (MED12).	[33]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Mediator of RNA polymerase II transcription subunit 12 (MED12).	[37]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Mediator of RNA polymerase II transcription subunit 12 (MED12).	[38]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Mediator of RNA polymerase II transcription subunit 12 (MED12).	[39]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Mediator of RNA polymerase II transcription subunit 12 (MED12).	[40]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Mediator of RNA polymerase II transcription subunit 12 (MED12).	[34]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Mediator of RNA polymerase II transcription subunit 12 (MED12).	[35]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Mediator of RNA polymerase II transcription subunit 12 (MED12).	[36]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Mediator of RNA polymerase II transcription subunit 12 (MED12).	[41]

References

• [1] Integrated genomic characterization of adrenocortical carcinoma.Nat Genet. 2014 Jun;46(6):607-12. doi: 10.1038/ng.2953. Epub 2014 Apr 20.
• [2] Somatic MED12 mutations in uterine leiomyosarcoma and colorectal cancer.Br J Cancer. 2012 Nov 6;107(10):1761-5. doi: 10.1038/bjc.2012.428. Epub 2012 Sep 20.
• [3] A recurrent mutation in MED12 leading to R961W causes Opitz-Kaveggia syndrome. Nat Genet. 2007 Apr;39(4):451-3. doi: 10.1038/ng1992. Epub 2007 Mar 4.
• [4] Clinicopathologic Features and Genetic Alterations of a Primary Osteosarcoma of the Uterine Corpus.Int J Gynecol Pathol. 2019 Sep;38(5):414-419. doi: 10.1097/PGP.0000000000000511.
• [5] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [6] Lujan-Fryns Syndrome (LFS): A Unique Combination of Hypernasality, Marfanoid Body Habitus, and Neuropsychiatric Issues, Presenting as Acute-Onset Dysphagia. Clin Med Insights Case Rep. 2016 Dec 4;9:115-118. doi: 10.4137/CCRep.S41083. eCollection 2016.
• [7] Complex karyotype in de novo acute myeloid leukemia: typical and atypical subtypes differ molecularly and clinically.Leukemia. 2019 Jul;33(7):1620-1634. doi: 10.1038/s41375-019-0390-3. Epub 2019 Feb 8.
• [8] Molecular biomarkers for uterine leiomyosarcoma and endometrial stromal sarcoma.Cancer Sci. 2018 Jun;109(6):1743-1752. doi: 10.1111/cas.13613. Epub 2018 May 23.
• [9] Mediator is a transducer of amyloid-precursor-protein-dependent nuclear signalling.EMBO Rep. 2011 Mar;12(3):216-22. doi: 10.1038/embor.2010.210. Epub 2011 Feb 4.
• [10] Mitochondrial Morphology, Dynamics, and Function in Human Pressure Overload or Ischemic Heart Disease With Preserved or Reduced Ejection Fraction.Circ Heart Fail. 2019 Feb;12(2):e005131. doi: 10.1161/CIRCHEARTFAILURE.118.005131.
• [11] Mutations in MED12 cause X-linked Ohdo syndrome. Am J Hum Genet. 2013 Mar 7;92(3):401-6. doi: 10.1016/j.ajhg.2013.01.007. Epub 2013 Feb 7.
• [12] Expression of CDK8 and CDK8-interacting Genes as Potential Biomarkers in Breast Cancer.Curr Cancer Drug Targets. 2015;15(8):739-49. doi: 10.2174/156800961508151001105814.
• [13] MED12 somatic mutations encompassing exon 2 associated with benign breast fibroadenomas and not breast carcinoma in Indian women.J Cell Biochem. 2019 Jan;120(1):182-191. doi: 10.1002/jcb.27293. Epub 2018 Sep 19.
• [14] De novo loss-of-function variants in X-linked MED12 are associated with Hardikar syndrome in females. Genet Med. 2021 Apr;23(4):637-644. doi: 10.1038/s41436-020-01031-7. Epub 2020 Nov 27.
• [15] Comprehensive analysis of the transcriptional profile of the Mediator complex across human cancer types.Oncotarget. 2016 Apr 26;7(17):23043-23055. doi: 10.18632/oncotarget.8469.
• [16] Depletion of Mediator Kinase Module Subunits Represses Superenhancer-Associated Genes in Colon Cancer Cells.Mol Cell Biol. 2018 May 15;38(11):e00573-17. doi: 10.1128/MCB.00573-17. Print 2018 Jun 1.
• [17] The association of a HOPA polymorphism with major depression and phobia.Compr Psychiatry. 2002 Sep-Oct;43(5):404-10. doi: 10.1053/comp.2002.33489.
• [18] Loss of MED12 Induces Tumor Dormancy in Human Epithelial Ovarian Cancer via Downregulation of EGFR.Cancer Res. 2018 Jul 1;78(13):3532-3543. doi: 10.1158/0008-5472.CAN-18-0134. Epub 2018 May 7.
• [19] Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity.Nat Biotechnol. 2016 Feb;34(2):155-63. doi: 10.1038/nbt.3391. Epub 2015 Nov 30.
• [20] Turner syndrome and schizophrenia: a further hint for the role of the X-chromosome in the pathogenesis of schizophrenic disorders.World J Biol Psychiatry. 2010 Mar;11(2 Pt 2):239-42. doi: 10.3109/15622970701599060.
• [21] Dysregulations of sonic hedgehog signaling in MED12-related X-linked intellectual disability disorders.Mol Genet Genomic Med. 2019 Apr;7(4):e00569. doi: 10.1002/mgg3.569. Epub 2019 Feb 6.
• [22] CDK8 Expression in Extrauterine Leiomyosarcoma Correlates With Tumor Stage and Progression.Appl Immunohistochem Mol Morphol. 2018 Mar;26(3):161-164. doi: 10.1097/PAI.0000000000000409.
• [23] MED12 exerts an emerging role in actin-mediated cytokinesis via LIMK2/cofilin pathway in NSCLC.Mol Cancer. 2019 May 9;18(1):93. doi: 10.1186/s12943-019-1020-4.
• [24] Somatic MED12 mutations in prostate cancer and uterine leiomyomas promote tumorigenesis through distinct mechanisms.Prostate. 2016 Jan;76(1):22-31. doi: 10.1002/pros.23092. Epub 2015 Sep 18.
• [25] MED12 mutations and NOTCH signalling in chronic lymphocytic leukaemia.Br J Haematol. 2017 Nov;179(3):421-429. doi: 10.1111/bjh.14869. Epub 2017 Aug 2.
• [26] Mediator links epigenetic silencing of neuronal gene expression with x-linked mental retardation.Mol Cell. 2008 Aug 8;31(3):347-59. doi: 10.1016/j.molcel.2008.05.023.
• [27] Mutational analysis of MED12 exon 2 in a spectrum of fibroepithelial tumours of the breast: implications for pathogenesis and histogenesis.Histopathology. 2016 Feb;68(3):433-41. doi: 10.1111/his.12764. Epub 2015 Aug 7.
• [28] 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.
• [29] Role of MED12 in transcription and human behavior.Pharmacogenomics. 2007 Aug;8(8):909-16. doi: 10.2217/14622416.8.8.909.
• [30] Two male sibs with severe micrognathia and a missense variant in MED12.Eur J Med Genet. 2016 Aug;59(8):367-72. doi: 10.1016/j.ejmg.2016.06.001. Epub 2016 Jun 7.
• [31] Blepharophimosis, short humeri, developmental delay and hirschsprung disease: expanding the phenotypic spectrum of MED12 mutations.Am J Med Genet A. 2014 Jul;164A(7):1821-5. doi: 10.1002/ajmg.a.36539. Epub 2014 Apr 8.
• [32] RAS signaling and anti-RAS therapy: lessons learned from genetically engineered mouse models, human cancer cells, and patient-related studies.Acta Biochim Biophys Sin (Shanghai). 2016 Jan;48(1):27-38. doi: 10.1093/abbs/gmv090. Epub 2015 Sep 7.
• [33] 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.
• [34] 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.
• [35] 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.
• [36] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [37] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [38] 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.
• [39] 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.
• [40] 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.
• [41] Cellular reactions to long-term volatile organic compound (VOC) exposures. Sci Rep. 2016 Dec 1;6:37842. doi: 10.1038/srep37842.