Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7CEIG0)

DOT Name	Myocyte-specific enhancer factor 2D (MEF2D)
Gene Name	MEF2D
Related Disease	B-cell neoplasm ( ) Acute leukaemia ( ) Acute lymphocytic leukaemia ( ) Advanced cancer ( ) Alzheimer disease ( ) Autoimmune disease ( ) Bone osteosarcoma ( ) Carcinoma of liver and intrahepatic biliary tract ( ) Cervical cancer ( ) Cervical carcinoma ( ) Chagas disease ( ) Chronic obstructive pulmonary disease ( ) Colorectal carcinoma ( ) Epithelial ovarian cancer ( ) Gastric cancer ( ) Glioma ( ) Hepatocellular carcinoma ( ) leukaemia ( ) Leukemia ( ) Liver cancer ( ) Lung cancer ( ) Lung carcinoma ( ) Malignant glioma ( ) Neoplasm ( ) Non-small-cell lung cancer ( ) Osteosarcoma ( ) Ovarian cancer ( ) Ovarian neoplasm ( ) Pancreatic cancer ( ) Parkinson disease ( ) Respiratory disease ( ) Stomach cancer ( ) Systemic lupus erythematosus ( ) Rhabdomyosarcoma ( ) Childhood acute lymphoblastic leukemia ( ) Leiomyosarcoma ( ) Small lymphocytic lymphoma ( )
UniProt ID	MEF2D_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
PDB ID	7X1N
Pfam ID	PF12347 ; PF00319
Sequence	MGRKKIQIQRITDERNRQVTFTKRKFGLMKKAYELSVLCDCEIALIIFNHSNKLFQYAST DMDKVLLKYTEYNEPHESRTNADIIETLRKKGFNGCDSPEPDGEDSLEQSPLLEDKYRRA SEELDGLFRRYGSTVPAPNFAMPVTVPVSNQSSLQFSNPSGSLVTPSLVTSSLTDPRLLS PQQPALQRNSVSPGLPQRPASAGAMLGGDLNSANGACPSPVGNGYVSARASPGLLPVANG NSLNKVIPAKSPPPPTHSTQLGAPSRKPDLRVITSQAGKGLMHHLTEDHLDLNNAQRLGV SQSTHSLTTPVVSVATPSLLSQGLPFSSMPTAYNTDYQLTSAELSSLPAFSSPGGLSLGN VTAWQQPQQPQQPQQPQPPQQQPPQPQQPQPQQPQQPQQPPQQQSHLVPVSLSNLIPGSP LPHVGAALTVTTHPHISIKSEPVSPSRERSPAPPPPAVFPAARPEPGDGLSSPAGGSYET GDRDDGRGDFGPTLGLLRPAPEPEAEGSAVKRMRLDTWTLK
Function	Transcriptional activator which binds specifically to the MEF2 element, 5'-YTA[AT](4)TAR-3', found in numerous muscle-specific, growth factor- and stress-induced genes. Mediates cellular functions not only in skeletal and cardiac muscle development, but also in neuronal differentiation and survival. Plays diverse roles in the control of cell growth, survival and apoptosis via p38 MAPK signaling in muscle-specific and/or growth factor-related transcription. Plays a critical role in the regulation of neuronal apoptosis.
KEGG Pathway	cGMP-PKG sig.ling pathway (hsa04022 ) Apelin sig.ling pathway (hsa04371 ) Parathyroid hormone synthesis, secretion and action (hsa04928 )
Reactome Pathway	Circadian Clock (R-HSA-400253 ) Myogenesis (R-HSA-525793 ) NGF-stimulated transcription (R-HSA-9031628 ) Heme signaling (R-HSA-9707616 ) Transcriptional activation of mitochondrial biogenesis (R-HSA-2151201 )

Molecular Interaction Atlas (MIA) of This DOT

37 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance
B-cell neoplasm	DISVY326	Definitive	Biomarker	[1]
Acute leukaemia	DISDQFDI	Strong	Altered Expression	[2]
Acute lymphocytic leukaemia	DISPX75S	Strong	Genetic Variation	[3]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[4]
Alzheimer disease	DISF8S70	Strong	Altered Expression	[5]
Autoimmune disease	DISORMTM	Strong	Genetic Variation	[6]
Bone osteosarcoma	DIST1004	Strong	Altered Expression	[7]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Strong	Biomarker	[8]
Cervical cancer	DISFSHPF	Strong	Biomarker	[9]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[9]
Chagas disease	DIS8KNVF	Strong	Biomarker	[10]
Chronic obstructive pulmonary disease	DISQCIRF	Strong	Altered Expression	[11]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[12]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[4]
Gastric cancer	DISXGOUK	Strong	Biomarker	[13]
Glioma	DIS5RPEH	Strong	Altered Expression	[14]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[15]
leukaemia	DISS7D1V	Strong	Genetic Variation	[16]
Leukemia	DISNAKFL	Strong	Genetic Variation	[16]
Liver cancer	DISDE4BI	Strong	Biomarker	[8]
Lung cancer	DISCM4YA	Strong	Altered Expression	[8]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[8]
Malignant glioma	DISFXKOV	Strong	Biomarker	[17]
Neoplasm	DISZKGEW	Strong	Biomarker	[4]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[11]
Osteosarcoma	DISLQ7E2	Strong	Altered Expression	[7]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[4]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[4]
Pancreatic cancer	DISJC981	Strong	Biomarker	[18]
Parkinson disease	DISQVHKL	Strong	Biomarker	[19]
Respiratory disease	DISGGAGJ	Strong	Biomarker	[11]
Stomach cancer	DISKIJSX	Strong	Biomarker	[13]
Systemic lupus erythematosus	DISI1SZ7	Strong	Genetic Variation	[6]
Rhabdomyosarcoma	DISNR7MS	moderate	Biomarker	[20]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Limited	Altered Expression	[21]
Leiomyosarcoma	DIS6COXM	Limited	Biomarker	[22]
Small lymphocytic lymphoma	DIS30POX	Limited	Altered Expression	[21]
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⏷ Show the Full List of 37 Disease(s)

Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Myocyte-specific enhancer factor 2D (MEF2D).	[23]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Myocyte-specific enhancer factor 2D (MEF2D).	[24]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Myocyte-specific enhancer factor 2D (MEF2D).	[25]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Myocyte-specific enhancer factor 2D (MEF2D).	[26]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Myocyte-specific enhancer factor 2D (MEF2D).	[27]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Myocyte-specific enhancer factor 2D (MEF2D).	[28]
Marinol	DM70IK5	Approved	Marinol increases the expression of Myocyte-specific enhancer factor 2D (MEF2D).	[29]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Myocyte-specific enhancer factor 2D (MEF2D).	[30]
Cocaine	DMSOX7I	Approved	Cocaine decreases the expression of Myocyte-specific enhancer factor 2D (MEF2D).	[31]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Myocyte-specific enhancer factor 2D (MEF2D).	[32]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Myocyte-specific enhancer factor 2D (MEF2D).	[34]
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⏷ Show the Full List of 11 Drug(s)

4 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 increases the methylation of Myocyte-specific enhancer factor 2D (MEF2D).	[33]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Myocyte-specific enhancer factor 2D (MEF2D).	[35]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Myocyte-specific enhancer factor 2D (MEF2D).	[36]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Myocyte-specific enhancer factor 2D (MEF2D).	[37]
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References

1	Down-regulation of miR-17 family expression in response to retinoic acid induced neuronal differentiation.Cell Signal. 2009 Dec;21(12):1837-45. doi: 10.1016/j.cellsig.2009.07.019. Epub 2009 Aug 8.
2	Paediatric patients with acute leukaemia and KMT2A (MLL) rearrangement show a distinctive expression pattern of histone deacetylases.Br J Haematol. 2018 Aug;182(4):542-553. doi: 10.1111/bjh.15436. Epub 2018 Jul 5.
3	Chromosomal translocation-mediated evasion from miRNA induces strong MEF2D fusion protein expression, causing inhibition of PAX5 transcriptional activity.Oncogene. 2019 Mar;38(13):2263-2274. doi: 10.1038/s41388-018-0573-9. Epub 2018 Nov 26.
4	Overexpression of MEF2D contributes to oncogenic malignancy and chemotherapeutic resistance in ovarian carcinoma.Am J Cancer Res. 2019 May 1;9(5):887-905. eCollection 2019.
5	-synuclein aggregation reduces nigral myocyte enhancer factor-2D in idiopathic and experimental Parkinson's disease.Neurobiol Dis. 2011 Jan;41(1):71-82. doi: 10.1016/j.nbd.2010.08.022. Epub 2010 Sep 9.
6	A rare regulatory variant in the MEF2D gene affects gene regulation and splicing and is associated with a SLE sub-phenotype in Swedish cohorts.Eur J Hum Genet. 2019 Mar;27(3):432-441. doi: 10.1038/s41431-018-0297-x. Epub 2018 Nov 20.
7	Long non-coding RNA EPIC1 inhibits viability and invasion of osteosarcoma cells by promoting MEF2D ubiquitylation.Int J Biol Macromol. 2019 May 1;128:566-573. doi: 10.1016/j.ijbiomac.2019.01.156. Epub 2019 Jan 28.
8	Absent expression of miR-30a promotes the growth of lung cancer cells by targeting MEF2D.Oncol Lett. 2018 Jul;16(1):1173-1179. doi: 10.3892/ol.2018.8719. Epub 2018 May 16.
9	Downregulation of miR-30a is associated with proliferation and invasion via targeting MEF2D in cervical cancer.Oncol Lett. 2017 Dec;14(6):7437-7442. doi: 10.3892/ol.2017.7114. Epub 2017 Oct 2.
10	Genes of the cGMP-PKG-Ca(2+) signaling pathway are alternatively spliced in cardiomyopathy: Role of RBFOX2.Biochim Biophys Acta Mol Basis Dis. 2020 Mar 1;1866(3):165620. doi: 10.1016/j.bbadis.2019.165620. Epub 2019 Nov 25.
11	Myocyte enhancer factor 2D provides a cross-talk between chronic inflammation and lung cancer.J Transl Med. 2017 Mar 24;15(1):65. doi: 10.1186/s12967-017-1168-x.
12	Myocyte enhancer factor 2D promotes colorectal cancer angiogenesis downstream of hypoxia-inducible factor 1.Cancer Lett. 2017 Aug 1;400:117-126. doi: 10.1016/j.canlet.2017.04.037. Epub 2017 May 4.
13	MEF2D/Wnt/-catenin pathway regulates the proliferation of gastric cancer cells and is regulated by microRNA-19.Tumour Biol. 2016 Jul;37(7):9059-69. doi: 10.1007/s13277-015-4766-3. Epub 2016 Jan 13.
14	Long noncoding RNA DLEU1 aggravates glioma progression via the miR-421/MEF2D axis.Onco Targets Ther. 2019 Jul 8;12:5405-5414. doi: 10.2147/OTT.S207542. eCollection 2019.
15	Disruption of SIRT7 Increases the Efficacy of Checkpoint Inhibitor via MEF2D Regulation of Programmed Cell Death 1 Ligand 1 in Hepatocellular Carcinoma Cells.Gastroenterology. 2020 Feb;158(3):664-678.e24. doi: 10.1053/j.gastro.2019.10.025. Epub 2019 Oct 31.
16	Genomic Profiling of Adult and Pediatric B-cell Acute Lymphoblastic Leukemia.EBioMedicine. 2016 Jun;8:173-183. doi: 10.1016/j.ebiom.2016.04.038. Epub 2016 May 13.
17	Myocyte enhancer factor 2D promotes tumorigenicity in malignant glioma cells.Tumour Biol. 2016 Jan;37(1):601-10. doi: 10.1007/s13277-015-3791-6. Epub 2015 Aug 4.
18	Overexpression and biological function of MEF2D in human pancreatic cancer.Am J Transl Res. 2017 Nov 15;9(11):4836-4847. eCollection 2017.
19	Salidroside protects dopaminergic neurons by regulating the mitochondrial MEF2D-ND6 pathway in the MPTP/MPP(+) -induced model of Parkinson's disease.J Neurochem. 2020 Apr;153(2):276-289. doi: 10.1111/jnc.14868. Epub 2019 Oct 27.
20	Loss of MEF2D expression inhibits differentiation and contributes to oncogenesis in rhabdomyosarcoma cells.Mol Cancer. 2013 Nov 27;12(1):150. doi: 10.1186/1476-4598-12-150.
21	MEF2D-BCL9 Fusion Gene Is Associated With High-Risk Acute B-Cell Precursor Lymphoblastic Leukemia in Adolescents.J Clin Oncol. 2016 Oct 1;34(28):3451-9. doi: 10.1200/JCO.2016.66.5547. Epub 2016 Aug 9.
22	Different class IIa HDACs repressive complexes regulate specific epigenetic responses related to cell survival in leiomyosarcoma cells.Nucleic Acids Res. 2020 Jan 24;48(2):646-664. doi: 10.1093/nar/gkz1120.
23	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.
24	Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
25	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.
26	Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
27	Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
28	Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
29	THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
30	Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
31	Gene expression in human hippocampus from cocaine abusers identifies genes which regulate extracellular matrix remodeling. PLoS One. 2007 Nov 14;2(11):e1187. doi: 10.1371/journal.pone.0001187.
32	Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
33	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.
34	Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
35	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.
36	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.
37	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.