Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTL0F3D6)

• DOT Name: RNA binding protein fox-1 homolog 3 (RBFOX3)
• Synonyms: Fox-1 homolog C; Neuronal nuclei antigen; NeuN antigen
• Gene Name: RBFOX3
• Related Disease:
  Childhood epilepsy with centrotemporal spikes
  Autism spectrum disorder
  Hepatocellular carcinoma
  Neoplasm
  Pervasive developmental disorder
  Respiratory syncytial virus infection
  Acute myelogenous leukaemia
  Neurodevelopmental disorder
  Advanced cancer
  Brain disease
  Epilepsy
  Lung cancer
  Lung carcinoma
• UniProt ID: RFOX3_HUMAN
• Pfam ID: PF12414 ; PF00076
• Sequence:
  MAQPYPPAQYPPPPQNGIPAEYAPPPPHPTQDYSGQTPVPTEHGMTLYTPAQTHPEQPGS
  EASTQPIAGTQTVPQTDEAAQTDSQPLHPSDPTEKQQPKRLHVSNIPFRFRDPDLRQMFG
  QFGKILDVEIIFNERGSKGFGFVTFETSSDADRAREKLNGTIVEGRKIEVNNATARVMTN
  KKTGNPYTNGWKLNPVVGAVYGPEFYAVTGFPYPTTGTAVAYRGAHLRGRGRAVYNTFRA
  APPPPPIPTYGAVVYQDGFYGAEIYGGYAAYRYAQPAAAAAAYSDSYGRVYAAADPYHHT
  IGPAATYSIGTM
• Function: Pre-mRNA alternative splicing regulator. Regulates alternative splicing of RBFOX2 to enhance the production of mRNA species that are targeted for nonsense-mediated decay (NMD).
• Reactome Pathway: NPAS4 regulates expression of target genes (R-HSA-9768919)

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Childhood epilepsy with centrotemporal spikes	DISKT2L5	Definitive	CausalMutation	[1]
Autism spectrum disorder	DISXK8NV	Strong	Biomarker	[2]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[3]
Neoplasm	DISZKGEW	Strong	Biomarker	[4]
Pervasive developmental disorder	DIS51975	Strong	Biomarker	[2]
Respiratory syncytial virus infection	DIS7FWHY	Strong	Altered Expression	[5]
Acute myelogenous leukaemia	DISCSPTN	moderate	Genetic Variation	[6]
Neurodevelopmental disorder	DIS372XH	moderate	Biomarker	[7]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[3]
Brain disease	DIS6ZC3X	Limited	Genetic Variation	[2]
Epilepsy	DISBB28L	Limited	Autosomal dominant	[8]
Lung cancer	DISCM4YA	Limited	Altered Expression	[9]
Lung carcinoma	DISTR26C	Limited	Altered Expression	[9]

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 RNA binding protein fox-1 homolog 3 (RBFOX3).	[10]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of RNA binding protein fox-1 homolog 3 (RBFOX3).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of RNA binding protein fox-1 homolog 3 (RBFOX3).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of RNA binding protein fox-1 homolog 3 (RBFOX3).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of RNA binding protein fox-1 homolog 3 (RBFOX3).	[11]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of RNA binding protein fox-1 homolog 3 (RBFOX3).	[13]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of RNA binding protein fox-1 homolog 3 (RBFOX3).	[14]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of RNA binding protein fox-1 homolog 3 (RBFOX3).	[15]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of RNA binding protein fox-1 homolog 3 (RBFOX3).	[16]
Alitretinoin	DMME8LH	Approved	Alitretinoin increases the expression of RNA binding protein fox-1 homolog 3 (RBFOX3).	[17]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of RNA binding protein fox-1 homolog 3 (RBFOX3).	[15]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of RNA binding protein fox-1 homolog 3 (RBFOX3).	[15]

References

• [1] Exome-wide analysis of mutational burden in patients with typical and atypical Rolandic epilepsy.Eur J Hum Genet. 2018 Feb;26(2):258-264. doi: 10.1038/s41431-017-0034-x. Epub 2018 Jan 22.
• [2] Neuronal Splicing Regulator RBFOX3 (NeuN) Regulates Adult Hippocampal Neurogenesis and Synaptogenesis.PLoS One. 2016 Oct 4;11(10):e0164164. doi: 10.1371/journal.pone.0164164. eCollection 2016.
• [3] RBFOX3 Regulates the Chemosensitivity of Cancer Cells to 5-Fluorouracil via the PI3K/AKT, EMT and Cytochrome-C/Caspase Pathways.Cell Physiol Biochem. 2018;46(4):1365-1380. doi: 10.1159/000489153. Epub 2018 Apr 18.
• [4] RBFOX3 Promotes Tumor Growth and Progression via hTERT Signaling and Predicts a Poor Prognosis in Hepatocellular Carcinoma.Theranostics. 2017 Jul 22;7(12):3138-3154. doi: 10.7150/thno.19506. eCollection 2017.
• [5] Respiratory syncytial virus prolifically infects N2a neuronal cells, leading to TLR4 and nucleolin protein modulations and RSV F protein co-localization with TLR4 and nucleolin.J Biomed Sci. 2018 Feb 10;25(1):13. doi: 10.1186/s12929-018-0416-6.
• [6] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [7] Chronic HIV-1 Tat and HIV reduce Rbfox3/NeuN: evidence for sex-related effects.Curr HIV Res. 2015;13(1):10-20. doi: 10.2174/1570162x13666150311163733.
• [8] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [9] Transforming Growth Factor--Induced RBFOX3 Inhibition Promotes Epithelial-Mesenchymal Transition of Lung Cancer Cells.Mol Cells. 2016 Aug 31;39(8):625-30. doi: 10.14348/molcells.2016.0150. Epub 2016 Jul 19.
• [10] 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.
• [11] Neuroprotective effects of glucomoringin-isothiocyanate against H(2)O(2)-Induced cytotoxicity in neuroblastoma (SH-SY5Y) cells. Neurotoxicology. 2019 Dec;75:89-104. doi: 10.1016/j.neuro.2019.09.008. Epub 2019 Sep 12.
• [12] 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.
• [13] 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.
• [14] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [15] 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.
• [16] Repetitive nicotine exposure leads to a more malignant and metastasis-prone phenotype of SCLC: a molecular insight into the importance of quitting smoking during treatment. Toxicol Sci. 2010 Aug;116(2):467-76. doi: 10.1093/toxsci/kfq138. Epub 2010 May 10.
• [17] Effects of all-trans and 9-cis retinoic acid on differentiating human neural stem cells in vitro. Toxicology. 2023 Mar 15;487:153461. doi: 10.1016/j.tox.2023.153461. Epub 2023 Feb 16.
• [18] 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.
• [19] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.