Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBHW3S9)

• DOT Name: Metastasis-associated protein MTA1 (MTA1)
• Gene Name: MTA1
• UniProt ID: MTA1_HUMAN
• PDB ID: 4BKX; 4PBY; 4PBZ; 4PC0; 5FXY; 5ICN; 6G16; 6ZRC; 6ZRD; 7AO8; 7AO9; 7AOA
• Pfam ID: PF01426 ; PF01448 ; PF00320 ; PF17226 ; PF00249
• Sequence:
  MAANMYRVGDYVYFENSSSNPYLIRRIEELNKTANGNVEAKVVCFYRRRDISSTLIALAD
  KHATLSVCYKAGPGADNGEEGEIEEEMENPEMVDLPEKLKHQLRHRELFLSRQLESLPAT
  HIRGKCSVTLLNETESLKSYLEREDFFFYSLVYDPQQKTLLADKGEIRVGNRYQADITDL
  LKEGEEDGRDQSRLETQVWEAHNPLTDKQIDQFLVVARSVGTFARALDCSSSVRQPSLHM
  SAAAASRDITLFHAMDTLHKNIYDISKAISALVPQGGPVLCRDEMEEWSASEANLFEEAL
  EKYGKDFTDIQQDFLPWKSLTSIIEYYYMWKTTDRYVQQKRLKAAEAESKLKQVYIPNYN
  KPNPNQISVNNVKAGVVNGTGAPGQSPGAGRACESCYTTQSYQWYSWGPPNMQCRLCASC
  WTYWKKYGGLKMPTRLDGERPGPNRSNMSPHGLPARSSGSPKFAMKTRQAFYLHTTKLTR
  IARRLCREILRPWHAARHPYLPINSAAIKAECTARLPEASQSPLVLKQAVRKPLEAVLRY
  LETHPRPPKPDPVKSVSSVLSSLTPAKVAPVINNGSPTILGKRSYEQHNGVDGNMKKRLL
  MPSRGLANHGQARHMGPSRNLLLNGKSYPTKVRLIRGGSLPPVKRRRMNWIDAPDDVFYM
  ATEETRKIRKLLSSSETKRAARRPYKPIALRQSQALPPRPPPPAPVNDEPIVIED
• Function: Transcriptional coregulator which can act as both a transcriptional corepressor and coactivator. Acts as a component of the histone deacetylase NuRD complex which participates in the remodeling of chromatin. In the NuRD complex, regulates transcription of its targets by modifying the acetylation status of the target chromatin and cofactor accessibility to the target DNA. In conjunction with other components of NuRD, acts as a transcriptional corepressor of BRCA1, ESR1, TFF1 and CDKN1A. Acts as a transcriptional coactivator of BCAS3, and SUMO2, independent of the NuRD complex. Stimulates the expression of WNT1 by inhibiting the expression of its transcriptional corepressor SIX3. Regulates p53-dependent and -independent DNA repair processes following genotoxic stress. Regulates the stability and function of p53/TP53 by inhibiting its ubiquitination by COP1 and MDM2 thereby regulating the p53-dependent DNA repair. Plays a role in the regulation of the circadian clock and is essential for the generation and maintenance of circadian rhythms under constant light and for normal entrainment of behavior to light-dark (LD) cycles. Positively regulates the CLOCK-BMAL1 heterodimer mediated transcriptional activation of its own transcription and the transcription of CRY1. Regulates deacetylation of BMAL1 by regulating SIRT1 expression, resulting in derepressing CRY1-mediated transcription repression. With TFCP2L1, promotes establishment and maintenance of pluripotency in embryonic stem cells (ESCs) and inhibits endoderm differentiation; [Isoform Short]: Binds to ESR1 and sequesters it in the cytoplasm and enhances its non-genomic responses.
• Tissue Specificity: Widely expressed. High expression in brain, liver, kidney, and cardiac muscle, ovaries, adrenal glands and virgin mammary glands. Higher in tumors than in adjacent normal tissue from the same individual. Up-regulated in a wide variety of cancers including breast, liver, ovarian, and colorectal cancer and its expression levels are closely correlated with tumor aggressiveness and metastasis.
• KEGG Pathway: ATP-dependent chromatin remodeling (hsa03082)
• Reactome Pathway:
  SUMOylation of transcription factors (R-HSA-3232118)
  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

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Metastasis-associated protein MTA1 (MTA1).	[1]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Metastasis-associated protein MTA1 (MTA1).	[6]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Metastasis-associated protein MTA1 (MTA1).	[18]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Metastasis-associated protein MTA1 (MTA1).	[18]

19 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 Metastasis-associated protein MTA1 (MTA1).	[2]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Metastasis-associated protein MTA1 (MTA1).	[3]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Metastasis-associated protein MTA1 (MTA1).	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Metastasis-associated protein MTA1 (MTA1).	[5]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Metastasis-associated protein MTA1 (MTA1).	[7]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Metastasis-associated protein MTA1 (MTA1).	[8]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Metastasis-associated protein MTA1 (MTA1).	[9]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Metastasis-associated protein MTA1 (MTA1).	[10]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the expression of Metastasis-associated protein MTA1 (MTA1).	[4]
Aspirin	DM672AH	Approved	Aspirin increases the expression of Metastasis-associated protein MTA1 (MTA1).	[11]
Mifepristone	DMGZQEF	Approved	Mifepristone decreases the expression of Metastasis-associated protein MTA1 (MTA1).	[12]
Sevoflurane	DMC9O43	Approved	Sevoflurane increases the expression of Metastasis-associated protein MTA1 (MTA1).	[13]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Metastasis-associated protein MTA1 (MTA1).	[14]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene decreases the expression of Metastasis-associated protein MTA1 (MTA1).	[2]
HMPL-004	DM29XGY	Phase 3	HMPL-004 decreases the expression of Metastasis-associated protein MTA1 (MTA1).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of Metastasis-associated protein MTA1 (MTA1).	[16]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Metastasis-associated protein MTA1 (MTA1).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Metastasis-associated protein MTA1 (MTA1).	[19]
2-chloroadenosine	DMYPQEW	Investigative	2-chloroadenosine decreases the expression of Metastasis-associated protein MTA1 (MTA1).	[20]

References

• [1] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [2] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [3] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [4] Arsenite and cadmium promote the development of mammary tumors. Carcinogenesis. 2020 Jul 14;41(7):1005-1014. doi: 10.1093/carcin/bgz176.
• [5] 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.
• [6] 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.
• [7] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [8] [Impact of arsenic trioxide on proliferation and metastasis of drug-resistant human ovarian carcinoma cell line]. Ai Zheng. 2002 Aug;21(8):863-7.
• [9] Zoledronate dysregulates fatty acid metabolism in renal tubular epithelial cells to induce nephrotoxicity. Arch Toxicol. 2018 Jan;92(1):469-485.
• [10] Elucidating progesterone effects in breast cancer: cross talk with PDGF signaling pathway in smooth muscle cell. J Cell Biochem. 2007 Jan 1;100(1):174-83. doi: 10.1002/jcb.21045.
• [11] Effects of aspirin on metastasis-associated gene expression detected by cDNA microarray. Acta Pharmacol Sin. 2004 Oct;25(10):1327-33.
• [12] Mifepristone induced progesterone withdrawal reveals novel regulatory pathways in human endometrium. Mol Hum Reprod. 2007 Sep;13(9):641-54.
• [13] The differential cancer growth associated with anaesthetics in a cancer xenograft model of mice: mechanisms and implications of postoperative cancer recurrence. Cell Biol Toxicol. 2023 Aug;39(4):1561-1575. doi: 10.1007/s10565-022-09747-9. Epub 2022 Aug 12.
• [14] Resveratrol enhances p53 acetylation and apoptosis in prostate cancer by inhibiting MTA1/NuRD complex. Int J Cancer. 2010 Apr 1;126(7):1538-48. doi: 10.1002/ijc.24928.
• [15] Andrographolide reduced VEGFA expression in hepatoma cancer cells by inactivating HIF-1: The involvement of JNK and MTA1/HDCA. Chem Biol Interact. 2017 Aug 1;273:228-236. doi: 10.1016/j.cbi.2017.06.024. Epub 2017 Jun 23.
• [16] Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.
• [17] The BET bromodomain inhibitor JQ1 suppresses growth of pancreatic ductal adenocarcinoma in patient-derived xenograft models. Oncogene. 2016 Feb 18;35(7):833-45.
• [18] 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.
• [19] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.
• [20] [nhibitory effect of adenosine analogues on invasion of human ovarian cancer cell line HO-8910PM]. Ai Zheng. 2004 Dec;23(12):1646-50.