Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT40PZ9R)

• DOT Name: Mediator of RNA polymerase II transcription subunit 27 (MED27)
• Synonyms: Cofactor required for Sp1 transcriptional activation subunit 8; CRSP complex subunit 8; Mediator complex subunit 27; P37 TRAP/SMCC/PC2 subunit; Transcriptional coactivator CRSP34
• Gene Name: MED27
• Related Disease:
  Medulloblastoma
  Neurodevelopmental disorder with spasticity, cataracts, and cerebellar hypoplasia
  Syndromic intellectual disability
  Bone osteosarcoma
  Osteosarcoma
  Adrenocortical carcinoma
  Aplasia cutis congenita
  Corpus callosum, agenesis of
  Melanoma
  Neoplasm
• UniProt ID: MED27_HUMAN
• PDB ID: 7EMF; 7ENA; 7ENC; 7ENJ; 7LBM; 7NVR; 8GXQ; 8GXS
• Pfam ID: PF11571
• Sequence:
  MADVINVSVNLEAFSQAISAIQALRSSVSRVFDCLKDGMRNKETLEGREKAFIAHFQDNL
  HSVNRDLNELERLSNLVGKPSENHPLHNSGLLSLDPVQDKTPLYSQLLQAYKWSNKLQYH
  AGLASGLLNQQSLKRSANQMGVSAKRRPKAQPTTLVLPPQYVDDVISRIDRMFPEMSIHL
  SRPNGTSAMLLVTLGKVLKVIVVMRSLFIDRTIVKGYNENVYTEDGKLDIWSKSNYQVFQ
  KVTDHATTALLHYQLPQMPDVVVRSFMTWLRSYIKLFQAPCQRCGKFLQDGLPPTWRDFR
  TLEAFHDTCRQ
• 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.
• 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

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Medulloblastoma	DISZD2ZL	Strong	Biomarker	[1]
Neurodevelopmental disorder with spasticity, cataracts, and cerebellar hypoplasia	DISKG4GG	Strong	Autosomal recessive	[2]
Syndromic intellectual disability	DISH7SDF	Supportive	Autosomal dominant	[3]
Bone osteosarcoma	DIST1004	Disputed	Biomarker	[4]
Osteosarcoma	DISLQ7E2	Disputed	Biomarker	[4]
Adrenocortical carcinoma	DISZF4HX	Limited	Altered Expression	[5]
Aplasia cutis congenita	DISMDAYM	Limited	Altered Expression	[5]
Corpus callosum, agenesis of	DISO9P40	Limited	Altered Expression	[5]
Melanoma	DIS1RRCY	Limited	Biomarker	[6]
Neoplasm	DISZKGEW	Limited	Biomarker	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Mediator of RNA polymerase II transcription subunit 27 (MED27).	[7]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Mediator of RNA polymerase II transcription subunit 27 (MED27).	[8]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Mediator of RNA polymerase II transcription subunit 27 (MED27).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Mediator of RNA polymerase II transcription subunit 27 (MED27).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Mediator of RNA polymerase II transcription subunit 27 (MED27).	[11]

References

• [1] CRABP-II methylation: a critical determinant of retinoic acid resistance of medulloblastoma cells.Mol Oncol. 2012 Feb;6(1):48-61. doi: 10.1016/j.molonc.2011.11.004. Epub 2011 Nov 25.
• [2] 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.
• [3] MED27 Variants Cause Developmental Delay, Dystonia, and Cerebellar Hypoplasia. Ann Neurol. 2021 Apr;89(4):828-833. doi: 10.1002/ana.26019. Epub 2021 Feb 8.
• [4] MicroRNA-18a inhibits cell growth and induces apoptosis in osteosarcoma by targeting MED27.Int J Oncol. 2018 Jul;53(1):329-338. doi: 10.3892/ijo.2018.4374. Epub 2018 Apr 16.
• [5] Silencing of MED27 inhibits adrenal cortical carcinogenesis by targeting the Wnt/-catenin signaling pathway and the epithelial-mesenchymal transition process.Biol Chem. 2018 May 24;399(6):593-602. doi: 10.1515/hsz-2017-0304.
• [6] MED27 promotes melanoma growth by targeting AKT/MAPK and NF-B/iNOS signaling pathways.Cancer Lett. 2016 Apr 1;373(1):77-87. doi: 10.1016/j.canlet.2016.01.005. Epub 2016 Jan 18.
• [7] The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
• [8] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [9] 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.
• [10] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [11] 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.