Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTIA6C79)

• DOT Name: Metastasis-associated protein MTA3 (MTA3)
• Gene Name: MTA3
• Related Disease:
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Clear cell renal carcinoma
  Gastroesophageal junction adenocarcinoma
  Glioma
  Head and neck cancer
  Head and neck carcinoma
  Hepatocellular carcinoma
  Neoplasm
  Non-small-cell lung cancer
  Epithelial ovarian cancer
  Ovarian cancer
  Ovarian neoplasm
  B-cell lymphoma
  Carcinoma
  Colorectal carcinoma
• UniProt ID: MTA3_HUMAN
• Pfam ID: PF01426 ; PF01448 ; PF00320 ; PF17226 ; PF00249
• Sequence:
  MAANMYRVGDYVYFENSSSNPYLIRRIEELNKTASGNVEAKVVCFYRRRDISNTLIMLAD
  KHAKEIEEESETTVEADLTDKQKHQLKHRELFLSRQYESLPATHIRGKCSVALLNETESV
  LSYLDKEDTFFYSLVYDPSLKTLLADKGEIRVGPRYQADIPEMLLEGESDEREQSKLEVK
  VWDPNSPLTDRQIDQFLVVARAVGTFARALDCSSSVRQPSLHMSAAAASRDITLFHAMDT
  LYRHSYDLSSAISVLVPLGGPVLCRDEMEEWSASEASLFEEALEKYGKDFNDIRQDFLPW
  KSLTSIIEYYYMWKTTDRYVQQKRLKAAEAESKLKQVYIPTYSKPNPNQISTSNGKPGAV
  NGAVGTTFQPQNPLLGRACESCYATQSHQWYSWGPPNMQCRLCAICWLYWKKYGGLKMPT
  QSEEEKLSPSPTTEDPRVRSHVSRQAMQGMPVRNTGSPKSAVKTRQAFFLHTTYFTKFAR
  QVCKNTLRLRQAARRPFVAINYAAIRAEYADRHAELSGSPLKSKSTRKPLACIIGYLEIH
  PAKKPNVIRSTPSLQTPTTKRMLTTPNHTSLSILGKRNYSHHNGLDELTCCVSD
• Function: Acts as a component of the histone deacetylase NuRD complex which participates in the remodeling of chromatin. Plays a role in maintenance of the normal epithelial architecture through the repression of SNAI1 transcription in a histone deacetylase-dependent manner, and thus the regulation of E-cadherin levels. Contributes to transcriptional repression by BCL6.
• Tissue Specificity: Expressed in germinal centers of lymphoid tissues. No expression in nonepithelial cells.
• KEGG Pathway: ATP-dependent chromatin remodeling (hsa03082)
• Reactome Pathway:
  ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression (R-HSA-427389)
  RNA Polymerase I Transcription Initiation (R-HSA-73762)
  Regulation of PTEN gene transcription (R-HSA-8943724)
  Potential therapeutics for SARS (R-HSA-9679191)
  HDACs deacetylate histones (R-HSA-3214815)

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Strong	Biomarker	[1]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[1]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[2]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[3]
Gastroesophageal junction adenocarcinoma	DISCVPML	Strong	Altered Expression	[4]
Glioma	DIS5RPEH	Strong	Biomarker	[5]
Head and neck cancer	DISBPSQZ	Strong	Biomarker	[6]
Head and neck carcinoma	DISOU1DS	Strong	Biomarker	[6]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[7]
Neoplasm	DISZKGEW	Strong	Biomarker	[6]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[8]
Epithelial ovarian cancer	DIS56MH2	moderate	Biomarker	[9]
Ovarian cancer	DISZJHAP	moderate	Biomarker	[9]
Ovarian neoplasm	DISEAFTY	moderate	Biomarker	[9]
B-cell lymphoma	DISIH1YQ	Disputed	Biomarker	[10]
Carcinoma	DISH9F1N	Limited	Altered Expression	[11]
Colorectal carcinoma	DIS5PYL0	Limited	Biomarker	[12]

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 Metastasis-associated protein MTA3 (MTA3).	[13]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Metastasis-associated protein MTA3 (MTA3).	[14]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Metastasis-associated protein MTA3 (MTA3).	[15]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Metastasis-associated protein MTA3 (MTA3).	[16]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Metastasis-associated protein MTA3 (MTA3).	[17]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Metastasis-associated protein MTA3 (MTA3).	[18]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Metastasis-associated protein MTA3 (MTA3).	[20]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Metastasis-associated protein MTA3 (MTA3).	[21]
Marinol	DM70IK5	Approved	Marinol increases the expression of Metastasis-associated protein MTA3 (MTA3).	[22]
Melphalan	DMOLNHF	Approved	Melphalan decreases the expression of Metastasis-associated protein MTA3 (MTA3).	[23]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Metastasis-associated protein MTA3 (MTA3).	[24]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Metastasis-associated protein MTA3 (MTA3).	[25]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Metastasis-associated protein MTA3 (MTA3).	[27]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Metastasis-associated protein MTA3 (MTA3).	[28]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Metastasis-associated protein MTA3 (MTA3).	[29]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Metastasis-associated protein MTA3 (MTA3).	[19]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Metastasis-associated protein MTA3 (MTA3).	[26]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Metastasis-associated protein MTA3 (MTA3).	[26]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid increases the phosphorylation of Metastasis-associated protein MTA3 (MTA3).	[30]

References

• [1] The Homeotic Protein SIX3 Suppresses Carcinogenesis and Metastasis through Recruiting the LSD1/NuRD(MTA3) Complex.Theranostics. 2018 Jan 1;8(4):972-989. doi: 10.7150/thno.22328. eCollection 2018.
• [2] Emerging roles of MTA family members in human cancers.Semin Oncol. 2003 Oct;30(5 Suppl 16):30-7. doi: 10.1053/j.seminoncol.2003.08.005.
• [3] MiR-367 regulates cell proliferation and metastasis by targeting metastasis-associated protein 3 (MTA3) in clear-cell renal cell carcinoma.Oncotarget. 2017 Jun 27;8(38):63084-63095. doi: 10.18632/oncotarget.18647. eCollection 2017 Sep 8.
• [4] The metastasis-associated gene MTA3, a component of the Mi-2/NuRD transcriptional repression complex, predicts prognosis of gastroesophageal junction adenocarcinoma.PLoS One. 2013 May 3;8(5):e62986. doi: 10.1371/journal.pone.0062986. Print 2013.
• [5] Expression of metastasis-associated protein 3 in human brain glioma related to tumor prognosis.Neurol Sci. 2015 Oct;36(10):1799-804. doi: 10.1007/s10072-015-2252-8. Epub 2015 May 23.
• [6] MTA3-SOX2 Module Regulates Cancer Stemness and Contributes to Clinical Outcomes of Tongue Carcinoma.Front Oncol. 2019 Aug 27;9:816. doi: 10.3389/fonc.2019.00816. eCollection 2019.
• [7] Catalpol inhibits cell proliferation, invasion and migration through regulating miR-22-3p/MTA3 signalling in hepatocellular carcinoma.Exp Mol Pathol. 2019 Aug;109:51-60. doi: 10.1016/j.yexmp.2019.104265. Epub 2019 May 27.
• [8] MiR-495 regulates proliferation and migration in NSCLC by targeting MTA3.Tumour Biol. 2014 Apr;35(4):3487-94. doi: 10.1007/s13277-013-1460-1. Epub 2013 Nov 29.
• [9] The metastasis-associated gene MTA1 is upregulated in advanced ovarian cancer, represses ERbeta, and enhances expression of oncogenic cytokine GRO.Cancer Biol Ther. 2008 Sep;7(9):1460-7. doi: 10.4161/cbt.7.9.6427. Epub 2008 Sep 11.
• [10] A new immunostain algorithm classifies diffuse large B-cell lymphoma into molecular subtypes with high accuracy.Clin Cancer Res. 2009 Sep 1;15(17):5494-502. doi: 10.1158/1078-0432.CCR-09-0113. Epub 2009 Aug 25.
• [11] The metastasis-associated gene MTA3 is downregulated in advanced endometrioid adenocarcinomas.Histol Histopathol. 2010 Nov;25(11):1447-56. doi: 10.14670/HH-25.1447.
• [12] Metastasis-associated protein 3 in colorectal cancer determines tumor recurrence and prognosis.Oncotarget. 2017 Jun 6;8(23):37164-37171. doi: 10.18632/oncotarget.16332.
• [13] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [14] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [15] 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.
• [16] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [17] Positive and negative transcriptional regulation of aromatase expression in human breast cancer tissue. J Steroid Biochem Mol Biol. 2005 May;95(1-5):17-23.
• [18] 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.
• [19] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [20] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [21] 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.
• [22] 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.
• [23] Bone marrow osteoblast damage by chemotherapeutic agents. PLoS One. 2012;7(2):e30758. doi: 10.1371/journal.pone.0030758. Epub 2012 Feb 17.
• [24] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [25] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [26] 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.
• [27] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.
• [28] 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.
• [29] Cystathionine metabolic enzymes play a role in the inflammation resolution of human keratinocytes in response to sub-cytotoxic formaldehyde exposure. Toxicol Appl Pharmacol. 2016 Nov 1;310:185-194.
• [30] 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.