Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6A9KHY)

• DOT Name: RNA-binding protein Nova-1 (NOVA1)
• Synonyms: Neuro-oncological ventral antigen 1; Onconeural ventral antigen 1; Paraneoplastic Ri antigen; Ventral neuron-specific protein 1
• Gene Name: NOVA1
• Related Disease:
  Melanoma
  Schizophrenia
  Thyroid cancer
  Thyroid gland carcinoma
  Thyroid tumor
  Adult glioblastoma
  Advanced cancer
  Astrocytoma
  Bone osteosarcoma
  Breast cancer
  Breast carcinoma
  Diabetic retinopathy
  Glioblastoma multiforme
  Glioma
  Head-neck squamous cell carcinoma
  Hepatocellular carcinoma
  Laryngeal disorder
  Non-small-cell lung cancer
  Osteosarcoma
  Riley-Day syndrome
  Gastric cancer
  Neoplasm
  Stomach cancer
  B-cell neoplasm
  Nervous system disease
  Type-1 diabetes
• UniProt ID: NOVA1_HUMAN
• PDB ID: 1DT4; 2ANN; 2ANR
• Pfam ID: PF00013
• Sequence:
  MMAAAPIQQNGTHTGVPIDLDPPDSRKRPLEAPPEAGSTKRTNTGEDGQYFLKVLIPSYA
  AGSIIGKGGQTIVQLQKETGATIKLSKSKDFYPGTTERVCLIQGTVEALNAVHGFIAEKI
  REMPQNVAKTEPVSILQPQTTVNPDRIKQTLPSSPTTTKSSPSDPMTTSRANQVKIIVPN
  STAGLIIGKGGATVKAVMEQSGAWVQLSQKPDGINLQERVVTVSGEPEQNRKAVELIIQK
  IQEDPQSGSCLNISYANVTGPVANSNPTGSPYANTAEVLPTAAAAAGLLGHANLAGVAAF
  PAVLSGFTGNDLVAITSALNTLASYGYNLNTLGLGLSQAAATGALAAAAASANPAAAAAN
  LLATYASEASASGSTAGGTAGTFALGSLAAATAATNGYFGAASPLAASAILGTEKSTDGS
  KDVVEIAVPENLVGAILGKGGKTLVEYQELTGARIQISKKGEFVPGTRNRKVTITGTPAA
  TQAAQYLITQRITYEQGVRAANPQKVG
• Function: Functions to regulate alternative splicing in neurons by binding pre-mRNA in a sequence-specific manner to activate exon inclusion or exclusion. It binds specifically to the sequences 5'-YCAY-3' and regulates splicing in only a subset of regulated exons. Binding to an exonic 5'-YCAY-3' cluster changes the protein complexes assembled on pre-mRNA, blocking U1 snRNP binding and exon inclusion, whereas binding to an intronic 5'-YCAY-3' cluster enhances spliceosome assembly and exon inclusion. Binding to 5'-YCAY-3' clusters results in a local and asymmetric action to regulate spliceosome assembly and alternative splicing in neurons. Binding to an exonic 5'-YCAY-3' cluster changed the protein complexes assembled on pre-mRNA, blocking U1 snRNP (small nuclear ribonucleoprotein) binding and exon inclusion, whereas binding to an intronic 5'-YCAY-3' cluster enhanced spliceosome assembly and exon inclusion. With NOVA1, they perform unique biological functions in different brain areas and cell types. Autoregulates its own expression by acting as a splicing repressor. Acts to activate the inclusion of exon E3A in the glycine receptor alpha-2 chain and of exon E9 in gamma-aminobutyric-acid receptor gamma-2 subunit via a distal downstream UCAU-rich intronic splicing enhancer. Acts to regulate a novel glycine receptor alpha-2 chain splice variant (alpha-2N) in developing spinal cord.
• Tissue Specificity: Expressed in cerebellum, brain stem, hippocampus, and frontal cortex.

Molecular Interaction Atlas (MIA) of This DOT

26 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Melanoma	DIS1RRCY	Definitive	Altered Expression	[1]
Schizophrenia	DISSRV2N	Definitive	Biomarker	[2]
Thyroid cancer	DIS3VLDH	Definitive	Biomarker	[3]
Thyroid gland carcinoma	DISMNGZ0	Definitive	Biomarker	[3]
Thyroid tumor	DISLVKMD	Definitive	Biomarker	[3]
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[4]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[5]
Astrocytoma	DISL3V18	Strong	Biomarker	[6]
Bone osteosarcoma	DIST1004	Strong	Altered Expression	[7]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[8]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[8]
Diabetic retinopathy	DISHGUJM	Strong	Altered Expression	[9]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[4]
Glioma	DIS5RPEH	Strong	Altered Expression	[4]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Biomarker	[10]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[11]
Laryngeal disorder	DISDKUQO	Strong	Altered Expression	[10]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[12]
Osteosarcoma	DISLQ7E2	Strong	Altered Expression	[7]
Riley-Day syndrome	DISJZHNP	Strong	Biomarker	[13]
Gastric cancer	DISXGOUK	moderate	Biomarker	[14]
Neoplasm	DISZKGEW	moderate	Altered Expression	[3]
Stomach cancer	DISKIJSX	moderate	Biomarker	[14]
B-cell neoplasm	DISVY326	Limited	Altered Expression	[15]
Nervous system disease	DISJ7GGT	Limited	Biomarker	[16]
Type-1 diabetes	DIS7HLUB	Limited	Altered Expression	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of RNA-binding protein Nova-1 (NOVA1).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of RNA-binding protein Nova-1 (NOVA1).	[29]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of RNA-binding protein Nova-1 (NOVA1).	[18]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of RNA-binding protein Nova-1 (NOVA1).	[19]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of RNA-binding protein Nova-1 (NOVA1).	[20]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of RNA-binding protein Nova-1 (NOVA1).	[21]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of RNA-binding protein Nova-1 (NOVA1).	[22]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of RNA-binding protein Nova-1 (NOVA1).	[23]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of RNA-binding protein Nova-1 (NOVA1).	[24]
Cytarabine	DMZD5QR	Approved	Cytarabine increases the expression of RNA-binding protein Nova-1 (NOVA1).	[25]
Mifepristone	DMGZQEF	Approved	Mifepristone increases the expression of RNA-binding protein Nova-1 (NOVA1).	[26]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of RNA-binding protein Nova-1 (NOVA1).	[27]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of RNA-binding protein Nova-1 (NOVA1).	[28]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of RNA-binding protein Nova-1 (NOVA1).	[30]

References

• [1] NOVA1 acts as an oncogene in melanoma via regulating FOXO3a expression.J Cell Mol Med. 2018 May;22(5):2622-2630. doi: 10.1111/jcmm.13527. Epub 2018 Mar 2.
• [2] TDP-43 and NOVA-1 RNA-binding proteins as competitive splicing regulators of the schizophrenia-associated TNIK gene.Biochim Biophys Acta Gene Regul Mech. 2019 Sep;1862(9):194413. doi: 10.1016/j.bbagrm.2019.194413. Epub 2019 Aug 2.
• [3] MicroRNA-592 suppresses the malignant phenotypes of thyroid cancer by regulating lncRNA NEAT1 and downregulating NOVA1.Int J Mol Med. 2019 Sep;44(3):1172-1182. doi: 10.3892/ijmm.2019.4278. Epub 2019 Jul 16.
• [4] MicroRNA-193a-5p exerts a tumor suppressor role in glioblastoma via modulating NOVA1.J Cell Biochem. 2019 Apr;120(4):6188-6197. doi: 10.1002/jcb.27906. Epub 2018 Oct 10.
• [5] NOVA1 directs PTBP1 to hTERT pre-mRNA and promotes telomerase activity in cancer cells.Oncogene. 2019 Apr;38(16):2937-2952. doi: 10.1038/s41388-018-0639-8. Epub 2018 Dec 19.
• [6] MiR-181b-5p downregulates NOVA1 to suppress proliferation, migration and invasion and promote apoptosis in astrocytoma.PLoS One. 2014 Oct 9;9(10):e109124. doi: 10.1371/journal.pone.0109124. eCollection 2014.
• [7] LncSNHG16 promotes proliferation and migration of osteosarcoma cells by targeting microRNA-146a-5p.Eur Rev Med Pharmacol Sci. 2019 Jan;23(1):96-104. doi: 10.26355/eurrev_201901_16753.
• [8] TATDN1 promotes the development and progression of breast cancer by targeting microRNA-140-3p.Eur Rev Med Pharmacol Sci. 2019 Jun;23(12):5293-5300. doi: 10.26355/eurrev_201906_18196.
• [9] MiRNA-138-5p protects the early diabetic retinopathy by regulating NOVA1.Eur Rev Med Pharmacol Sci. 2019 Sep;23(18):7749-7756. doi: 10.26355/eurrev_201909_18984.
• [10] NOVA1 induction by inflammation and NOVA1 suppression by epigenetic regulation in head and neck squamous cell carcinoma.Sci Rep. 2019 Aug 2;9(1):11231. doi: 10.1038/s41598-019-47755-8.
• [11] RNA binding protein Nova1 promotes tumor growth in vivo and its potential mechanism as an oncogene may due to its interaction with GABA(A) Receptor-2.J Biomed Sci. 2016 Oct 12;23(1):71. doi: 10.1186/s12929-016-0288-6.
• [12] NOVA1 regulates hTERT splicing and cell growth in non-small cell lung cancer.Nat Commun. 2018 Aug 6;9(1):3112. doi: 10.1038/s41467-018-05582-x.
• [13] MicroRNA screening identifies a link between NOVA1 expression and a low level of IKAP in familial dysautonomia.Dis Model Mech. 2016 Aug 1;9(8):899-909. doi: 10.1242/dmm.025841. Epub 2016 Jun 29.
• [14] Implications of NOVA1 suppression within the microenvironment of gastric cancer: association with immune cell dysregulation.Gastric Cancer. 2017 May;20(3):438-447. doi: 10.1007/s10120-016-0623-3. Epub 2016 Jun 18.
• [15] Roles of miR-494 in Intervertebral Disk Degeneration and the Related Mechanism.World Neurosurg. 2018 Dec 30:S1878-8750(18)32921-8. doi: 10.1016/j.wneu.2018.12.098. Online ahead of print.
• [16] Crystal structures of Nova-1 and Nova-2 K-homology RNA-binding domains.Structure. 1999 Feb 15;7(2):191-203. doi: 10.1016/S0969-2126(99)80025-2.
• [17] 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.
• [18] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [19] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [20] Effect of ovarian steroids on gene expression profile in human uterine microvascular endothelial cells. Fertil Steril. 2009 Aug;92(2):709-21.
• [21] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [22] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [23] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [24] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [25] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [26] Mifepristone induced progesterone withdrawal reveals novel regulatory pathways in human endometrium. Mol Hum Reprod. 2007 Sep;13(9):641-54.
• [27] 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.
• [28] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [29] 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.
• [30] 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.