Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTGH7N4C)

• DOT Name: Protein LYRIC (MTDH)
• Synonyms: 3D3/LYRIC; Astrocyte elevated gene-1 protein; AEG-1; Lysine-rich CEACAM1 co-isolated protein; Metadherin; Metastasis adhesion protein
• Gene Name: MTDH
• UniProt ID: LYRIC_HUMAN
• PDB ID: 4QMG
• Pfam ID: PF15686
• Sequence:
  MAARSWQDELAQQAEEGSARLREMLSVGLGFLRTELGLDLGLEPKRYPGWVILVGTGALG
  LLLLFLLGYGWAAACAGARKKRRSPPRKREEAAAVPAAAPDDLALLKNLRSEEQKKKNRK
  KLSEKPKPNGRTVEVAEGEAVRTPQSVTAKQPPEIDKKNEKSKKNKKKSKSDAKAVQNSS
  RHDGKEVDEGAWETKISHREKRQQRKRDKVLTDSGSLDSTIPGIENTITVTTEQLTTASF
  PVGSKKNKGDSHLNVQVSNFKSGKGDSTLQVSSGLNENLTVNGGGWNEKSVKLSSQISAG
  EEKWNSVSPASAGKRKTEPSAWSQDTGDANTNGKDWGRSWSDRSIFSGIGSTAEPVSQST
  TSDYQWDVSRNQPYIDDEWSGLNGLSSADPNSDWNAPAEEWGNWVDEERASLLKSQEPIP
  DDQKVSDDDKEKGEGALPTGKSKKKKKKKKKQGEDNSTAQDTEELEKEIREDLPVNTSKT
  RPKQEKAFSLKTISTSDPAEVLVKNSQPIKTLPPATSTEPSVILSKSDSDKSSSQVPPIL
  QETDKSKSNTKQNSVPPSQTKSETSWESPKQIKKKKKARRET
• Function: Down-regulates SLC1A2/EAAT2 promoter activity when expressed ectopically. Activates the nuclear factor kappa-B (NF-kappa-B) transcription factor. Promotes anchorage-independent growth of immortalized melanocytes and astrocytes which is a key component in tumor cell expansion. Promotes lung metastasis and also has an effect on bone and brain metastasis, possibly by enhancing the seeding of tumor cells to the target organ endothelium. Induces chemoresistance.
• Tissue Specificity: Widely expressed with highest levels in muscle-dominating organs such as skeletal muscle, heart, tongue and small intestine and in endocrine glands such as thyroid and adrenal gland. Overexpressed in various cancers including breast, brain, prostate, melanoma and glioblastoma multiforme.

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Protein LYRIC (MTDH).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Protein LYRIC (MTDH).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Protein LYRIC (MTDH).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Protein LYRIC (MTDH).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Protein LYRIC (MTDH).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Protein LYRIC (MTDH).	[6]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Protein LYRIC (MTDH).	[7]
Cidofovir	DMA13GD	Approved	Cidofovir decreases the expression of Protein LYRIC (MTDH).	[5]
Ifosfamide	DMCT3I8	Approved	Ifosfamide decreases the expression of Protein LYRIC (MTDH).	[5]
Clodronate	DM9Y6X7	Approved	Clodronate decreases the expression of Protein LYRIC (MTDH).	[5]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Protein LYRIC (MTDH).	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Protein LYRIC (MTDH).	[10]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Protein LYRIC (MTDH).	[11]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Protein LYRIC (MTDH).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Protein LYRIC (MTDH).	[9]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Protein LYRIC (MTDH).	[9]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid decreases the phosphorylation of Protein LYRIC (MTDH).	[13]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] 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.
• [3] 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.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] Transcriptomics hit the target: monitoring of ligand-activated and stress response pathways for chemical testing. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):7-18.
• [6] 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.
• [7] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [8] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [9] 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.
• [10] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [11] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [12] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [13] Functional lipidomics: Palmitic acid impairs hepatocellular carcinoma development by modulating membrane fluidity and glucose metabolism. Hepatology. 2017 Aug;66(2):432-448. doi: 10.1002/hep.29033. Epub 2017 Jun 16.