Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTN36Q6U)

• DOT Name: Non-POU domain-containing octamer-binding protein (NONO)
• Synonyms: NonO protein; 54 kDa nuclear RNA- and DNA-binding protein; p54(nrb); p54nrb; 55 kDa nuclear protein; NMT55; DNA-binding p52/p100 complex, 52 kDa subunit
• Gene Name: NONO
• Related Disease:
  Gallbladder carcinoma
  X-linked syndromic intellectual disability
  Abdominal aortic aneurysm
  Acute erythroid leukemia
  Acute monocytic leukemia
  Adult acute monocytic leukemia
  Advanced cancer
  Autism, susceptibility to, 15
  Breast adenocarcinoma
  Carcinoma of liver and intrahepatic biliary tract
  Clear cell renal carcinoma
  Colorectal carcinoma
  Ebstein anomaly
  Epilepsy
  Esophageal squamous cell carcinoma
  Hypopituitarism
  Intellectual disability
  Left ventricular noncompaction
  Liver cancer
  Melanoma
  Metastatic malignant neoplasm
  Neoplasm with perivascular epithelioid cell differentiation
  Papillary renal cell carcinoma
  Renal cell carcinoma
  Schizophrenia
  Syndromic X-linked intellectual disability 34
  Triple negative breast cancer
  Wilms tumor
  Breast cancer
  Breast carcinoma
  Hepatocellular carcinoma
  Rheumatoid arthritis
  Amyotrophic lateral sclerosis
  Breast neoplasm
  Castration-resistant prostate carcinoma
  Colon adenocarcinoma
  Frontotemporal dementia
  Gastric cancer
  Pick disease
  Stomach cancer
  X-linked dystonia-parkinsonism
• UniProt ID: NONO_HUMAN
• PDB ID: 3SDE; 5IFM; 6WMZ; 7LRQ; 7LRU; 7PU5
• Pfam ID: PF08075 ; PF00076
• Sequence:
  MQSNKTFNLEKQNHTPRKHHQHHHQQQHHQQQQQQPPPPPIPANGQQASSQNEGLTIDLK
  NFRKPGEKTFTQRSRLFVGNLPPDITEEEMRKLFEKYGKAGEVFIHKDKGFGFIRLETRT
  LAEIAKVELDNMPLRGKQLRVRFACHSASLTVRNLPQYVSNELLEEAFSVFGQVERAVVI
  VDDRGRPSGKGIVEFSGKPAARKALDRCSEGSFLLTTFPRPVTVEPMDQLDDEEGLPEKL
  VIKNQQFHKEREQPPRFAQPGSFEYEYAMRWKALIEMEKQQQDQVDRNIKEAREKLEMEM
  EAARHEHQVMLMRQDLMRRQEELRRMEELHNQEVQKRKQLELRQEEERRRREEEMRRQQE
  EMMRRQQEGFKGTFPDAREQEIRMGQMAMGGAMGINNRGAMPPAPVPAGTPAPPGPATMM
  PDGTLGLTPPTTERFGQAATMEGIGAIGGTPPAFNRAAPGAEFAPNKRRRY
• Function: DNA- and RNA binding protein, involved in several nuclear processes. Binds the conventional octamer sequence in double-stranded DNA. Also binds single-stranded DNA and RNA at a site independent of the duplex site. Involved in pre-mRNA splicing, probably as a heterodimer with SFPQ. Interacts with U5 snRNA, probably by binding to a purine-rich sequence located on the 3' side of U5 snRNA stem 1b. Together with PSPC1, required for the formation of nuclear paraspeckles. The SFPQ-NONO heteromer associated with MATR3 may play a role in nuclear retention of defective RNAs. The SFPQ-NONO heteromer may be involved in DNA unwinding by modulating the function of topoisomerase I/TOP1. The SFPQ-NONO heteromer may be involved in DNA non-homologous end joining (NHEJ) required for double-strand break repair and V(D)J recombination and may stabilize paired DNA ends. In vitro, the complex strongly stimulates DNA end joining, binds directly to the DNA substrates and cooperates with the Ku70/G22P1-Ku80/XRCC5 (Ku) dimer to establish a functional preligation complex. NONO is involved in transcriptional regulation. The SFPQ-NONO-NR5A1 complex binds to the CYP17 promoter and regulates basal and cAMP-dependent transcriptional activity. NONO binds to an enhancer element in long terminal repeats of endogenous intracisternal A particles (IAPs) and activates transcription. Regulates the circadian clock by repressing the transcriptional activator activity of the CLOCK-BMAL1 heterodimer. Important for the functional organization of GABAergic synapses. Plays a specific and important role in the regulation of synaptic RNAs and GPHN/gephyrin scaffold structure, through the regulation of GABRA2 transcript. Plays a key role during neuronal differentiation by recruiting TET1 to genomic loci and thereby regulating 5-hydroxymethylcytosine levels. Plays a role in the regulation of DNA virus-mediated innate immune response by assembling into the HDP-RNP complex, a complex that serves as a platform for IRF3 phosphorylation and subsequent innate immune response activation through the cGAS-STING pathway. Promotes activation of the cGAS-STING pathway in response to HIV-2 infection: acts by interacting with HIV-2 Capsid protein p24, thereby promoting detection of viral DNA by CGAS, leading to CGAS-mediated inmmune activation. In contrast, the weak interaction with HIV-1 Capsid protein p24 does not allow activation of the cGAS-STING pathway.
• Tissue Specificity: Heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas. Also found in a number of breast tumor cell lines.

Molecular Interaction Atlas (MIA) of This DOT

41 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Gallbladder carcinoma	DISD6ACL	Definitive	Biomarker	[1]
X-linked syndromic intellectual disability	DISG1YOH	Definitive	X-linked	[2]
Abdominal aortic aneurysm	DISD06OF	Strong	Altered Expression	[3]
Acute erythroid leukemia	DISZFC1O	Strong	Biomarker	[4]
Acute monocytic leukemia	DIS28NEL	Strong	Biomarker	[4]
Adult acute monocytic leukemia	DISG6BLX	Strong	Biomarker	[4]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[5]
Autism, susceptibility to, 15	DISYCG6A	Strong	X-linked	[6]
Breast adenocarcinoma	DISMPHJ0	Strong	Biomarker	[7]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Strong	Biomarker	[8]
Clear cell renal carcinoma	DISBXRFJ	Strong	Genetic Variation	[9]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[10]
Ebstein anomaly	DISO3NHV	Strong	Biomarker	[11]
Epilepsy	DISBB28L	Strong	Biomarker	[12]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[13]
Hypopituitarism	DIS1QT3G	Strong	Altered Expression	[11]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[11]
Left ventricular noncompaction	DISJ4QEG	Strong	Genetic Variation	[11]
Liver cancer	DISDE4BI	Strong	Biomarker	[8]
Melanoma	DIS1RRCY	Strong	Altered Expression	[14]
Metastatic malignant neoplasm	DIS86UK6	Strong	Altered Expression	[7]
Neoplasm with perivascular epithelioid cell differentiation	DIS8V0NT	Strong	Genetic Variation	[15]
Papillary renal cell carcinoma	DIS25HBV	Strong	Biomarker	[16]
Renal cell carcinoma	DISQZ2X8	Strong	Genetic Variation	[9]
Schizophrenia	DISSRV2N	Strong	Altered Expression	[17]
Syndromic X-linked intellectual disability 34	DISQRH96	Strong	X-linked	[18]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[19]
Wilms tumor	DISB6T16	Strong	Biomarker	[20]
Breast cancer	DIS7DPX1	moderate	Biomarker	[21]
Breast carcinoma	DIS2UE88	moderate	Biomarker	[21]
Hepatocellular carcinoma	DIS0J828	moderate	Biomarker	[8]
Rheumatoid arthritis	DISTSB4J	Disputed	Altered Expression	[22]
Amyotrophic lateral sclerosis	DISF7HVM	Limited	Biomarker	[23]
Breast neoplasm	DISNGJLM	Limited	Biomarker	[24]
Castration-resistant prostate carcinoma	DISVGAE6	Limited	Biomarker	[25]
Colon adenocarcinoma	DISDRE0J	Limited	Biomarker	[26]
Frontotemporal dementia	DISKYHXL	Limited	Biomarker	[23]
Gastric cancer	DISXGOUK	Limited	Biomarker	[27]
Pick disease	DISP6X50	Limited	Biomarker	[23]
Stomach cancer	DISKIJSX	Limited	Biomarker	[27]
X-linked dystonia-parkinsonism	DIS5TT9O	Limited	Biomarker	[28]

3 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 Non-POU domain-containing octamer-binding protein (NONO).	[29]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Non-POU domain-containing octamer-binding protein (NONO).	[35]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Non-POU domain-containing octamer-binding protein (NONO).	[36]

10 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 Non-POU domain-containing octamer-binding protein (NONO).	[30]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Non-POU domain-containing octamer-binding protein (NONO).	[31]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Non-POU domain-containing octamer-binding protein (NONO).	[32]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Non-POU domain-containing octamer-binding protein (NONO).	[33]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Non-POU domain-containing octamer-binding protein (NONO).	[34]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Non-POU domain-containing octamer-binding protein (NONO).	[37]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Non-POU domain-containing octamer-binding protein (NONO).	[38]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of Non-POU domain-containing octamer-binding protein (NONO).	[39]
biochanin A	DM0HPWY	Investigative	biochanin A decreases the expression of Non-POU domain-containing octamer-binding protein (NONO).	[40]
ORG2058	DMH1M6N	Investigative	ORG2058 decreases the expression of Non-POU domain-containing octamer-binding protein (NONO).	[41]

References

• [1] Long non-coding RNA SSTR5-AS1 facilitates gemcitabine resistance via stabilizing NONO in gallbladder carcinoma.Biochem Biophys Res Commun. 2020 Feb 19;522(4):952-959. doi: 10.1016/j.bbrc.2019.10.104. Epub 2019 Dec 4.
• [2] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [3] Silencing of NONO inhibits abdominal aortic aneurysm in apolipoprotein E-knockout mice via collagen deposition and inflammatory inhibition.J Cell Mol Med. 2019 Nov;23(11):7449-7461. doi: 10.1111/jcmm.14613. Epub 2019 Sep 11.
• [4] Knockdown of p54nrb inhibits migration, invasion and TNF- release of human acute monocytic leukemia THP1 cells.Oncol Rep. 2016 Jun;35(6):3742-8. doi: 10.3892/or.2016.4756. Epub 2016 Apr 20.
• [5] PLAIDOH: a novel method for functional prediction of long non-coding RNAs identifies cancer-specific LncRNA activities.BMC Genomics. 2019 Feb 15;20(1):137. doi: 10.1186/s12864-019-5497-4.
• [6] Intellectual disability and non-compaction cardiomyopathy with a de novo NONO mutation identified by exome sequencing. Eur J Hum Genet. 2016 Nov;24(11):1635-1638. doi: 10.1038/ejhg.2016.72. Epub 2016 Jun 22.
• [7] Loss of expression of a 55 kDa nuclear protein (nmt55) in estrogen receptor-negative human breast cancer.Diagn Mol Pathol. 1997 Aug;6(4):209-21. doi: 10.1097/00019606-199708000-00005.
• [8] Splicing Regulator p54(nrb) /Non-POU Domain-Containing Octamer-Binding Protein Enhances Carcinogenesis Through Oncogenic Isoform Switch of MYC Box-Dependent Interacting Protein 1 in Hepatocellular Carcinoma.Hepatology. 2020 Aug;72(2):548-568. doi: 10.1002/hep.31062. Epub 2020 Mar 25.
• [9] Xp11.2 translocation renal neoplasm with features of TFE3 rearrangement associated renal cell carcinoma and Xp11 translocation renal mesenchymal tumor with melanocytic differentiation harboring NONO-TFE3 fusion gene.Pathol Res Pract. 2019 Sep;215(9):152521. doi: 10.1016/j.prp.2019.152521. Epub 2019 Jun 27.
• [10] Long noncoding RNA GAPLINC promotes invasion in colorectal cancer by targeting SNAI2 through binding with PSF and NONO.Oncotarget. 2016 Jul 5;7(27):42183-42194. doi: 10.18632/oncotarget.9741.
• [11] Expanding the genetic and clinical spectrum of the NONO-associated X-linked intellectual disability syndrome.Am J Med Genet A. 2019 May;179(5):792-796. doi: 10.1002/ajmg.a.61091. Epub 2019 Feb 17.
• [12] Protocadherin 19 (PCDH19) interacts with paraspeckle protein NONO to co-regulate gene expression with estrogen receptor alpha (ER).Hum Mol Genet. 2017 Jun 1;26(11):2042-2052. doi: 10.1093/hmg/ddx094.
• [13] Downregulation of NONO induces apoptosis, suppressing growth and invasion in esophageal squamous cell carcinoma.Oncol Rep. 2018 Jun;39(6):2575-2583. doi: 10.3892/or.2018.6334. Epub 2018 Mar 27.
• [14] p54nrb is a new regulator of progression of malignant melanoma.Carcinogenesis. 2011 Aug;32(8):1176-82. doi: 10.1093/carcin/bgr103. Epub 2011 Jun 3.
• [15] Melanotic PEComa of the Sinonasal Mucosa With NONO-TFE3 Fusion: An Elusive Mimic of Sinonasal Melanoma.Am J Surg Pathol. 2017 May;41(5):717-722. doi: 10.1097/PAS.0000000000000778.
• [16] Fusion of splicing factor genes PSF and NonO (p54nrb) to the TFE3 gene in papillary renal cell carcinoma.Oncogene. 1997 Oct;15(18):2233-9. doi: 10.1038/sj.onc.1201394.
• [17] Prefrontal cortex shotgun proteome analysis reveals altered calcium homeostasis and immune system imbalance in schizophrenia.Eur Arch Psychiatry Clin Neurosci. 2009 Apr;259(3):151-63. doi: 10.1007/s00406-008-0847-2. Epub 2009 Jan 22.
• [18] NONO couples the circadian clock to the cell cycle. Proc Natl Acad Sci U S A. 2013 Jan 29;110(5):1592-9. doi: 10.1073/pnas.1213317110. Epub 2012 Dec 24.
• [19] IGFBP-3 interacts with NONO and SFPQ in PARP-dependent DNA damage repair in triple-negative breast cancer.Cell Mol Life Sci. 2019 May;76(10):2015-2030. doi: 10.1007/s00018-019-03033-4. Epub 2019 Feb 6.
• [20] A Children's Oncology Group and TARGET initiative exploring the genetic landscape of Wilms tumor.Nat Genet. 2017 Oct;49(10):1487-1494. doi: 10.1038/ng.3940. Epub 2017 Aug 21.
• [21] RNA-binding protein NONO promotes breast cancer proliferation by post-transcriptional regulation of SKP2 and E2F8.Cancer Sci. 2020 Jan;111(1):148-159. doi: 10.1111/cas.14240. Epub 2019 Dec 11.
• [22] P54/nrb prompts rheumatoid arthritis progression mainly by transcriptionally activating NF-B signaling.Pharmazie. 2017 May 1;72(5):260-264. doi: 10.1691/ph.2017.6904.
• [23] Cerebral ischemia induces the aggregation of proteins linked to neurodegenerative diseases.Sci Rep. 2018 Feb 9;8(1):2701. doi: 10.1038/s41598-018-21063-z.
• [24] p54(nrb)/NONO regulates lipid metabolism and breast cancer growth through SREBP-1A.Oncogene. 2016 Mar 17;35(11):1399-410. doi: 10.1038/onc.2015.197. Epub 2015 Jul 6.
• [25] Overexpression of p54(nrb)/NONO induces differential EPHA6 splicing and contributes to castration-resistant prostate cancer growth.Oncotarget. 2018 Jan 8;9(12):10510-10524. doi: 10.18632/oncotarget.24063. eCollection 2018 Feb 13.
• [26] NONO and RALY proteins are required for YB-1 oxaliplatin induced resistance in colon adenocarcinoma cell lines.Mol Cancer. 2011 Nov 25;10:145. doi: 10.1186/1476-4598-10-145.
• [27] Ets-1 promoter-associated noncoding RNA regulates the NONO/ERG/Ets-1 axis to drive gastric cancer progression.Oncogene. 2018 Aug;37(35):4871-4886. doi: 10.1038/s41388-018-0302-4. Epub 2018 May 18.
• [28] AFX1 and p54nrb: fine mapping, genomic structure, and exclusion as candidate genes of X-linked dystonia parkinsonism.Hum Genet. 1997 Oct;100(5-6):569-72. doi: 10.1007/s004390050553.
• [29] 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.
• [30] 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.
• [31] 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.
• [32] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [33] 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.
• [34] Quantitative proteomic analysis of HepG2 cells treated with quercetin suggests IQGAP1 involved in quercetin-induced regulation of cell proliferation and migration. OMICS. 2009 Apr;13(2):93-103. doi: 10.1089/omi.2008.0075.
• [35] 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.
• [36] 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.
• [37] 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.
• [38] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [39] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.
• [40] Mechanisms of the growth inhibitory effects of the isoflavonoid biochanin A on LNCaP cells and xenografts. Prostate. 2002 Aug 1;52(3):201-12.
• [41] The antiproliferative effects of progestins in T47D breast cancer cells are tempered by progestin induction of the ETS transcription factor Elf5. Mol Endocrinol. 2010 Jul;24(7):1380-92. doi: 10.1210/me.2009-0516. Epub 2010 Jun 2.