Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYVG3NM)

• DOT Name: N-myc-interactor (NMI)
• Synonyms: Nmi; N-myc and STAT interactor
• Gene Name: NMI
• Related Disease:
  Adult glioblastoma
  Gastric cancer
  Glioblastoma multiforme
  Glioma
  Melanoma
  Neoplasm
  Stomach cancer
  Tuberculosis
  Colorectal carcinoma
  Epithelial ovarian cancer
  Hepatocellular carcinoma
  Lung carcinoma
  Ovarian cancer
  Ovarian neoplasm
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Chronic hepatitis B virus infection
  Hepatitis B virus infection
  Lung cancer
• UniProt ID: NMI_HUMAN
• Pfam ID: PF07334 ; PF07292
• Sequence:
  MEADKDDTQQILKEHSPDEFIKDEQNKGLIDEITKKNIQLKKEIQKLETELQEATKEFQI
  KEDIPETKMKFLSVETPENDSQLSNISCSFQVSSKVPYEIQKGQALITFEKEEVAQNVVS
  MSKHHVQIKDVNLEVTAKPVPLNSGVRFQVYVEVSKMKINVTEIPDTLREDQMRDKLELS
  FSKSRNGGGEVDRVDYDRQSGSAVITFVEIGVADKILKKKEYPLYINQTCHRVTVSPYTE
  IHLKKYQIFSGTSKRTVLLTGMEGIQMDEEIVEDLINIHFQRAKNGGGEVDVVKCSLGQP
  HIAYFEE
• Function: Acts as a signaling pathway regulator involved in innate immune system response. In response to interleukin 2/IL2 and interferon IFN-gamma/IFNG, interacts with signal transducer and activator of transcription/STAT which activate the transcription of downstream genes involved in a multitude of signals for development and homeostasis. Enhances the recruitment of CBP/p300 coactivators to STAT1 and STAT5, resulting in increased STAT1- and STAT5-dependent transcription. In response to interferon IFN-alpha, associates in a complex with signaling pathway regulator IFI35 to regulate immune response; the complex formation prevents proteasome-mediated degradation of IFI35. In complex with IFI35, inhibits virus-triggered type I IFN-beta production when ubiquitinated by ubiquitin-protein ligase TRIM21. In complex with IFI35, negatively regulates nuclear factor NF-kappa-B signaling by inhibiting the nuclear translocation, activation and transcription of NF-kappa-B subunit p65/RELA, resulting in the inhibition of endothelial cell proliferation, migration and re-endothelialization of injured arteries. Negatively regulates virus-triggered type I interferon/IFN production by inducing proteosome-dependent degradation of IRF7, a transcriptional regulator of type I IFN, thereby interfering with cellular antiviral responses. Beside its role as an intracellular signaling pathway regulator, also functions extracellularly as damage-associated molecular patterns (DAMPs) to promote inflammation, when actively released by macrophage to the extracellular space during cell injury or pathogen invasion. Macrophage-secreted NMI activates NF-kappa-B signaling in adjacent macrophages through Toll-like receptor 4/TLR4 binding and activation, thereby inducing NF-kappa-B translocation from the cytoplasm into the nucleus which promotes the release of pro-inflammatory cytokines.
• Tissue Specificity: Expressed in adult spleen, liver, and kidney . Expressed in fetal thymus, liver, placenta, spleen, lung, and kidney but not brain . Expressed in macrophages .
• Reactome Pathway: SARS-CoV-1 activates/modulates innate immune responses (R-HSA-9692916)

Molecular Interaction Atlas (MIA) of This DOT

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[1]
Gastric cancer	DISXGOUK	Strong	Biomarker	[2]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[1]
Glioma	DIS5RPEH	Strong	Biomarker	[1]
Melanoma	DIS1RRCY	Strong	Biomarker	[3]
Neoplasm	DISZKGEW	Strong	Biomarker	[4]
Stomach cancer	DISKIJSX	Strong	Biomarker	[2]
Tuberculosis	DIS2YIMD	Strong	Biomarker	[5]
Colorectal carcinoma	DIS5PYL0	moderate	Altered Expression	[4]
Epithelial ovarian cancer	DIS56MH2	moderate	Genetic Variation	[6]
Hepatocellular carcinoma	DIS0J828	moderate	Altered Expression	[7]
Lung carcinoma	DISTR26C	moderate	Biomarker	[8]
Ovarian cancer	DISZJHAP	moderate	Genetic Variation	[6]
Ovarian neoplasm	DISEAFTY	moderate	Genetic Variation	[6]
Breast cancer	DIS7DPX1	Limited	Biomarker	[9]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[9]
Breast neoplasm	DISNGJLM	Limited	Altered Expression	[10]
Chronic hepatitis B virus infection	DISHL4NT	Limited	Biomarker	[11]
Hepatitis B virus infection	DISLQ2XY	Limited	Biomarker	[11]
Lung cancer	DISCM4YA	Limited	Biomarker	[12]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	N-myc-interactor (NMI) decreases the response to substance of Cisplatin.	[30]

19 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 N-myc-interactor (NMI).	[13]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of N-myc-interactor (NMI).	[14]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of N-myc-interactor (NMI).	[15]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of N-myc-interactor (NMI).	[16]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of N-myc-interactor (NMI).	[17]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of N-myc-interactor (NMI).	[18]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of N-myc-interactor (NMI).	[19]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of N-myc-interactor (NMI).	[20]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of N-myc-interactor (NMI).	[21]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of N-myc-interactor (NMI).	[22]
Azacitidine	DMTA5OE	Approved	Azacitidine increases the expression of N-myc-interactor (NMI).	[23]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of N-myc-interactor (NMI).	[22]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of N-myc-interactor (NMI).	[22]
OTX-015	DMI8RG1	Phase 1/2	OTX-015 decreases the expression of N-myc-interactor (NMI).	[24]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of N-myc-interactor (NMI).	[25]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of N-myc-interactor (NMI).	[26]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of N-myc-interactor (NMI).	[27]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of N-myc-interactor (NMI).	[28]
Butanoic acid	DMTAJP7	Investigative	Butanoic acid decreases the expression of N-myc-interactor (NMI).	[29]

References

• [1] High expression of N-myc (and STAT) interactor predicts poor prognosis and promotes tumor growth in human glioblastoma.Oncotarget. 2015 Mar 10;6(7):4901-19. doi: 10.18632/oncotarget.3208.
• [2] Multi-marker analysis of genomic annotation on gastric cancer GWAS data from Chinese populations.Gastric Cancer. 2019 Jan;22(1):60-68. doi: 10.1007/s10120-018-0841-y. Epub 2018 Jun 1.
• [3] Nmi (N-Myc interactor) inhibits Wnt/beta-catenin signaling and retards tumor growth.Int J Cancer. 2009 Aug 1;125(3):556-64. doi: 10.1002/ijc.24276.
• [4] NMI promotes cell proliferation through TGF/Smad pathway by upregulating STAT1 in colorectal cancer.J Cell Physiol. 2020 Jan;235(1):429-441. doi: 10.1002/jcp.28983. Epub 2019 Jun 23.
• [5] Interleukin-32 induces caspase-independent apoptosis mediated by N-Myc interactor in macrophages infected with Mycobacterium tuberculosis.FEBS J. 2019 Feb;286(3):572-583. doi: 10.1111/febs.14717. Epub 2018 Dec 26.
• [6] Tagging single-nucleotide polymorphisms in candidate oncogenes and susceptibility to ovarian cancer.Br J Cancer. 2009 Mar 24;100(6):993-1001. doi: 10.1038/sj.bjc.6604947. Epub 2009 Feb 24.
• [7] NMI promotes hepatocellular carcinoma progression via BDKRB2 and MAPK/ERK pathway.Oncotarget. 2017 Feb 14;8(7):12174-12185. doi: 10.18632/oncotarget.14556.
• [8] Etoposide induced NMI promotes cell apoptosis by activating the ARF-p53 signaling pathway in lung carcinoma.Biochem Biophys Res Commun. 2018 Jan 1;495(1):368-374. doi: 10.1016/j.bbrc.2017.10.010. Epub 2017 Oct 10.
• [9] Regulatory network reconstruction of five essential microRNAs for survival analysis in breast cancer by integrating miRNA and mRNA expression datasets.Funct Integr Genomics. 2019 Jul;19(4):645-658. doi: 10.1007/s10142-019-00670-7. Epub 2019 Mar 12.
• [10] microRNA-29 negatively regulates EMT regulator N-myc interactor in breast cancer.Mol Cancer. 2014 Aug 29;13:200. doi: 10.1186/1476-4598-13-200.
• [11] N-myc and STAT interactor correlates with severity and prognosis in acute-on-chronic liver failure of hepatitis B virus.J Gastroenterol Hepatol. 2019 Oct;34(10):1800-1808. doi: 10.1111/jgh.14634. Epub 2019 Mar 7.
• [12] Downregulation of NMI promotes tumor growth and predicts poor prognosis in human lung adenocarcinomas.Mol Cancer. 2017 Oct 12;16(1):158. doi: 10.1186/s12943-017-0705-9.
• [13] 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.
• [14] 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.
• [15] Benzodithiophenes potentiate differentiation of acute promyelocytic leukemia cells by lowering the threshold for ligand-mediated corepressor/coactivator exchange with retinoic acid receptor alpha and enhancing changes in all-trans-retinoic acid-regulated gene expression. Cancer Res. 2005 Sep 1;65(17):7856-65. doi: 10.1158/0008-5472.CAN-05-1056.
• [16] 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.
• [17] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [18] Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells. Toxicol Appl Pharmacol. 2009 Nov 1;240(3):355-66.
• [19] 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.
• [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] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [22] 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.
• [23] Differential regulation of the p73 cistrome by mammalian target of rapamycin reveals transcriptional programs of mesenchymal differentiation and tumorigenesis. Proc Natl Acad Sci U S A. 2011 Feb 1;108(5):2076-81. doi: 10.1073/pnas.1011936108. Epub 2011 Jan 18.
• [24] Comprehensive transcriptome profiling of BET inhibitor-treated HepG2 cells. PLoS One. 2022 Apr 29;17(4):e0266966. doi: 10.1371/journal.pone.0266966. eCollection 2022.
• [25] Genome-wide transcriptional and functional analysis of human T lymphocytes treated with benzo[alpha]pyrene. Int J Mol Sci. 2018 Nov 17;19(11).
• [26] 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.
• [27] Comparison of transcriptome expression alterations by chronic exposure to low-dose bisphenol A in different subtypes of breast cancer cells. Toxicol Appl Pharmacol. 2019 Dec 15;385:114814. doi: 10.1016/j.taap.2019.114814. Epub 2019 Nov 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] MS4A3-HSP27 target pathway reveals potential for haematopoietic disorder treatment in alimentary toxic aleukia. Cell Biol Toxicol. 2023 Feb;39(1):201-216. doi: 10.1007/s10565-021-09639-4. Epub 2021 Sep 28.
• [30] Gene expression analysis using human cancer xenografts to identify novel predictive marker genes for the efficacy of 5-fluorouracil-based drugs. Cancer Sci. 2006 Jun;97(6):510-22. doi: 10.1111/j.1349-7006.2006.00204.x.