Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8Q4U8Y)

• DOT Name: Mesoderm-specific transcript homolog protein (MEST)
• Synonyms: EC 3.-.-.-; Paternally-expressed gene 1 protein
• Gene Name: MEST
• Related Disease:
  Autism
  Barth syndrome
  Breast cancer
  Breast carcinoma
  Cervical cancer
  Cervical carcinoma
  Cervical Intraepithelial neoplasia
  Chronic kidney disease
  Hepatocellular carcinoma
  High blood pressure
  IgA nephropathy
  Intrahepatic cholangiocarcinoma
  Leiomyoma
  Lung adenocarcinoma
  Male infertility
  Neoplasm
  Obesity
  Oligospermia
  Trichohepatoenteric syndrome
  Uterine fibroids
  Chronic renal failure
  End-stage renal disease
  Fetal growth restriction
  Invasive breast carcinoma
  Advanced cancer
  Metastatic malignant neoplasm
  Breast neoplasm
  Carcinoma
  Colon cancer
  Colon carcinoma
  Epithelial ovarian cancer
  Lung cancer
  Lung carcinoma
  Non-small-cell lung cancer
  Ovarian cancer
  Ovarian neoplasm
  Small-cell lung cancer
• UniProt ID: MEST_HUMAN
• EC Number: 3.-.-.-
• Pfam ID: PF00561
• Sequence:
  MVRRDRLRRMREWWVQVGLLAVPLLAAYLHIPPPQLSPALHSWKSSGKFFTYKGLRIFYQ
  DSVGVVGSPEIVVLLHGFPTSSYDWYKIWEGLTLRFHRVIALDFLGFGFSDKPRPHHYSI
  FEQASIVEALLRHLGLQNRRINLLSHDYGDIVAQELLYRYKQNRSGRLTIKSLCLSNGGI
  FPETHRPLLLQKLLKDGGVLSPILTRLMNFFVFSRGLTPVFGPYTRPSESELWDMWAGIR
  NNDGNLVIDSLLQYINQRKKFRRRWVGALASVTIPIHFIYGPLDPVNPYPEFLELYRKTL
  PRSTVSILDDHISHYPQLEDPMGFLNAYMGFINSF
• Tissue Specificity: Highly expressed in hydatidiform moles, but barely expressed in dermoid cysts. Biallelic expression is detected in blood lymphocytes. Seems to imprinted in an isoform-specific manner rather than in a tissue-specific manner in lymphocytes. Isoform 1 is expressed only from the paternal allele. Isoform 2 is expressed from both the paternal allele and the maternal allele.

Molecular Interaction Atlas (MIA) of This DOT

37 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autism	DISV4V1Z	Strong	Genetic Variation	[1]
Barth syndrome	DISDI4KU	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Cervical cancer	DISFSHPF	Strong	Posttranslational Modification	[4]
Cervical carcinoma	DIST4S00	Strong	Posttranslational Modification	[4]
Cervical Intraepithelial neoplasia	DISXP757	Strong	Posttranslational Modification	[4]
Chronic kidney disease	DISW82R7	Strong	Genetic Variation	[5]
Hepatocellular carcinoma	DIS0J828	Strong	Posttranslational Modification	[6]
High blood pressure	DISY2OHH	Strong	Biomarker	[7]
IgA nephropathy	DISZ8MTK	Strong	Genetic Variation	[8]
Intrahepatic cholangiocarcinoma	DIS6GOC8	Strong	Genetic Variation	[4]
Leiomyoma	DISLDDFN	Strong	Altered Expression	[9]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[10]
Male infertility	DISY3YZZ	Strong	Posttranslational Modification	[11]
Neoplasm	DISZKGEW	Strong	Altered Expression	[3]
Obesity	DIS47Y1K	Strong	Biomarker	[12]
Oligospermia	DIS6YJF3	Strong	Posttranslational Modification	[13]
Trichohepatoenteric syndrome	DISL3ODF	Strong	Biomarker	[14]
Uterine fibroids	DISBZRMJ	Strong	Altered Expression	[9]
Chronic renal failure	DISGG7K6	moderate	Biomarker	[15]
End-stage renal disease	DISXA7GG	moderate	Biomarker	[15]
Fetal growth restriction	DIS5WEJ5	moderate	Altered Expression	[16]
Invasive breast carcinoma	DISANYTW	moderate	Altered Expression	[17]
Advanced cancer	DISAT1Z9	Disputed	Biomarker	[18]
Metastatic malignant neoplasm	DIS86UK6	Disputed	Biomarker	[18]
Breast neoplasm	DISNGJLM	Limited	Altered Expression	[17]
Carcinoma	DISH9F1N	Limited	Biomarker	[17]
Colon cancer	DISVC52G	Limited	Biomarker	[17]
Colon carcinoma	DISJYKUO	Limited	Biomarker	[17]
Epithelial ovarian cancer	DIS56MH2	Limited	Biomarker	[19]
Lung cancer	DISCM4YA	Limited	Biomarker	[10]
Lung carcinoma	DISTR26C	Limited	Biomarker	[10]
Non-small-cell lung cancer	DIS5Y6R9	Limited	Biomarker	[10]
Ovarian cancer	DISZJHAP	Limited	Biomarker	[19]
Ovarian neoplasm	DISEAFTY	Limited	Biomarker	[19]
Small-cell lung cancer	DISK3LZD	Limited	Biomarker	[10]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Topotecan	DMP6G8T	Approved	Mesoderm-specific transcript homolog protein (MEST) affects the response to substance of Topotecan.	[39]
Mitoxantrone	DMM39BF	Approved	Mesoderm-specific transcript homolog protein (MEST) affects the response to substance of Mitoxantrone.	[39]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Mesoderm-specific transcript homolog protein (MEST).	[20]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Mesoderm-specific transcript homolog protein (MEST).	[21]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Mesoderm-specific transcript homolog protein (MEST).	[22]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Mesoderm-specific transcript homolog protein (MEST).	[23]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Mesoderm-specific transcript homolog protein (MEST).	[24]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Mesoderm-specific transcript homolog protein (MEST).	[25]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Mesoderm-specific transcript homolog protein (MEST).	[26]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Mesoderm-specific transcript homolog protein (MEST).	[27]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Mesoderm-specific transcript homolog protein (MEST).	[29]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Mesoderm-specific transcript homolog protein (MEST).	[30]
Seocalcitol	DMKL9QO	Phase 3	Seocalcitol decreases the expression of Mesoderm-specific transcript homolog protein (MEST).	[31]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Mesoderm-specific transcript homolog protein (MEST).	[33]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Mesoderm-specific transcript homolog protein (MEST).	[34]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Mesoderm-specific transcript homolog protein (MEST).	[36]
Paraquat	DMR8O3X	Investigative	Paraquat decreases the expression of Mesoderm-specific transcript homolog protein (MEST).	[37]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Folic acid	DMEMBJC	Approved	Folic acid decreases the methylation of Mesoderm-specific transcript homolog protein (MEST).	[28]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Mesoderm-specific transcript homolog protein (MEST).	[32]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Mesoderm-specific transcript homolog protein (MEST).	[35]
Lead acetate	DML0GZ2	Investigative	Lead acetate decreases the methylation of Mesoderm-specific transcript homolog protein (MEST).	[38]

References

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• [2] Expression of Peg1 (Mest) in the developing mouse heart: involvement in trabeculation.Dev Dyn. 2002 Oct;225(2):212-5. doi: 10.1002/dvdy.10142.
• [3] ZFP57 suppress proliferation of breast cancer cells through down-regulation of MEST-mediated Wnt/-catenin signalling pathway.Cell Death Dis. 2019 Feb 20;10(3):169. doi: 10.1038/s41419-019-1335-5.
• [4] PEG1/MEST and IGF2 DNA methylation in CIN and in cervical cancer.Clin Transl Oncol. 2014 Mar;16(3):266-72. doi: 10.1007/s12094-013-1067-4. Epub 2013 Jun 18.
• [5] IgA nephropathy: an update.Curr Opin Nephrol Hypertens. 2017 May;26(3):165-171. doi: 10.1097/MNH.0000000000000312.
• [6] Epigenetic silencing of miR-335 and its host gene MEST in hepatocellular carcinoma.Int J Oncol. 2013 Feb;42(2):411-8. doi: 10.3892/ijo.2012.1724. Epub 2012 Nov 30.
• [7] DNA Methylation of Candidate Genes (ACE II, IFN-, AGTR 1, CKG, ADD1, SCNN1B and TLR2) in Essential Hypertension: A Systematic Review and Quantitative Evidence Synthesis.Int J Environ Res Public Health. 2019 Dec 1;16(23):4829. doi: 10.3390/ijerph16234829.
• [8] Tubular atrophy/interstitial fibrosis scores of Oxford classification combinded with proteinuria level at biopsy provides earlier risk prediction in lgA nephropathy.Sci Rep. 2017 Apr 24;7(1):1100. doi: 10.1038/s41598-017-01223-3.
• [9] Imprinting and expression status of isoforms 1 and 2 of PEG1/MEST gene in uterine leiomyoma.Gynecol Obstet Invest. 2010;70(2):120-5. doi: 10.1159/000301555. Epub 2010 Mar 26.
• [10] Loss of imprinting of PEG1/MEST in lung cancer cell lines.Oncol Rep. 2004 Dec;12(6):1273-8.
• [11] Impairment of sperm DNA methylation in male infertility: a meta-analytic study.Andrology. 2017 Jul;5(4):695-703. doi: 10.1111/andr.12379.
• [12] Mesoderm-specific transcript localization in the ER and ER-lipid droplet interface supports a role in adipocyte hypertrophy.J Cell Biochem. 2018 Mar;119(3):2636-2645. doi: 10.1002/jcb.26429. Epub 2017 Dec 4.
• [13] DNA methylation in spermatozoa as a prospective marker in andrology.Andrology. 2013 Sep;1(5):731-40. doi: 10.1111/j.2047-2927.2013.00118.x.
• [14] Syndrome Differentiation of IgA Nephropathy Based on Clinicopathological Parameters: A Decision Tree Model.Evid Based Complement Alternat Med. 2017;2017:2697560. doi: 10.1155/2017/2697560. Epub 2017 Mar 26.
• [15] A validation study of crescents in predicting ESRD in patients with IgA nephropathy.J Transl Med. 2018 May 3;16(1):115. doi: 10.1186/s12967-018-1488-5.
• [16] Unbalanced placental expression of imprinted genes in human intrauterine growth restriction.Placenta. 2006 Jun-Jul;27(6-7):540-9. doi: 10.1016/j.placenta.2005.07.004. Epub 2005 Aug 24.
• [17] Promoter switch: a novel mechanism causing biallelic PEG1/MEST expression in invasive breast cancer.Hum Mol Genet. 2002 Jun 1;11(12):1449-53. doi: 10.1093/hmg/11.12.1449.
• [18] MEST induces Twist-1-mediated EMT through STAT3 activation in breast cancers.Cell Death Differ. 2019 Dec;26(12):2594-2606. doi: 10.1038/s41418-019-0322-9. Epub 2019 Mar 22.
• [19] Candidate DNA methylation drivers of acquired cisplatin resistance in ovarian cancer identified by methylome and expression profiling.Oncogene. 2012 Oct 18;31(42):4567-76. doi: 10.1038/onc.2011.611. Epub 2012 Jan 16.
• [20] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [21] 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.
• [22] 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.
• [23] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [24] 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.
• [25] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [26] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [27] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [28] The effect of folic acid deficiency on Mest/Peg1 in neural tube defects. Int J Neurosci. 2021 May;131(5):468-477. doi: 10.1080/00207454.2020.1750386. Epub 2020 Apr 16.
• [29] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [30] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [31] Expression profiling in squamous carcinoma cells reveals pleiotropic effects of vitamin D3 analog EB1089 signaling on cell proliferation, differentiation, and immune system regulation. Mol Endocrinol. 2002 Jun;16(6):1243-56.
• [32] 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.
• [33] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [34] 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.
• [35] MEST mediates the impact of prenatal bisphenol A exposure on long-term body weight development. Clin Epigenetics. 2018 Apr 20;10:58. doi: 10.1186/s13148-018-0478-z. eCollection 2018.
• [36] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [37] An in vitro strategy using multiple human induced pluripotent stem cell-derived models to assess the toxicity of chemicals: A case study on paraquat. Toxicol In Vitro. 2022 Jun;81:105333. doi: 10.1016/j.tiv.2022.105333. Epub 2022 Feb 16.
• [38] In vitro lead exposure changes DNA methylation and expression of IGF2 and PEG1/MEST. Toxicol In Vitro. 2015 Apr;29(3):544-50. doi: 10.1016/j.tiv.2015.01.002. Epub 2015 Jan 14.
• [39] 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.