Details of Drug Off-Target (DOT)

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

• DOT Name: WW domain-containing oxidoreductase
• Synonyms: EC 1.1.1.-; Fragile site FRA16D oxidoreductase; Short chain dehydrogenase/reductase family 41C member 1
• Gene Name: WWOX
• Related Disease:
  Infantile spasm
  Autosomal recessive spinocerebellar ataxia 12
  Developmental and epileptic encephalopathy, 28
  46,XY partial gonadal dysgenesis
  Undetermined early-onset epileptic encephalopathy
• UniProt ID: WWOX_HUMAN
• PDB ID: 1WMV
• EC Number: 1.1.1.-
• Pfam ID: PF00106 ; PF00397
• Sequence:
  MAALRYAGLDDTDSEDELPPGWEERTTKDGWVYYANHTEEKTQWEHPKTGKRKRVAGDLP
  YGWEQETDENGQVFFVDHINKRTTYLDPRLAFTVDDNPTKPTTRQRYDGSTTAMEILQGR
  DFTGKVVVVTGANSGIGFETAKSFALHGAHVILACRNMARASEAVSRILEEWHKAKVEAM
  TLDLALLRSVQHFAEAFKAKNVPLHVLVCNAATFALPWSLTKDGLETTFQVNHLGHFYLV
  QLLQDVLCRSAPARVIVVSSESHRFTDINDSLGKLDFSRLSPTKNDYWAMLAYNRSKLCN
  ILFSNELHRRLSPRGVTSNAVHPGNMMYSNIHRSWWVYTLLFTLARPFTKSMQQGAATTV
  YCAAVPELEGLGGMYFNNCCRCMPSPEAQSEETARTLWALSERLIQERLGSQSG
• Function: Putative oxidoreductase. Acts as a tumor suppressor and plays a role in apoptosis. Required for normal bone development. May function synergistically with p53/TP53 to control genotoxic stress-induced cell death. Plays a role in TGFB1 signaling and TGFB1-mediated cell death. May also play a role in tumor necrosis factor (TNF)-mediated cell death. Inhibits Wnt signaling, probably by sequestering DVL2 in the cytoplasm.
• Tissue Specificity: Widely expressed. Strongly expressed in testis, prostate, and ovary. Overexpressed in cancer cell lines. Isoform 5 and isoform 6 may only be expressed in tumor cell lines.
• Reactome Pathway:
  Negative regulation of activity of TFAP2 (AP-2) family transcription factors (R-HSA-8866904)
  Activation of the TFAP2 (AP-2) family of transcription factors (R-HSA-8866907)
  Nuclear signaling by ERBB4 (R-HSA-1251985)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Infantile spasm	DISZSKDG	Definitive	Autosomal recessive	[1]
Autosomal recessive spinocerebellar ataxia 12	DIS0TD3S	Strong	Autosomal recessive	[2]
Developmental and epileptic encephalopathy, 28	DISNN0OR	Strong	Autosomal recessive	[3]
46,XY partial gonadal dysgenesis	DISMNH0C	Supportive	Autosomal dominant	[4]
Undetermined early-onset epileptic encephalopathy	DISISEI2	Supportive	Autosomal dominant	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cycloheximide	DMGDA3C	Investigative	WW domain-containing oxidoreductase affects the response to substance of Cycloheximide.	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of WW domain-containing oxidoreductase.	[6]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of WW domain-containing oxidoreductase.	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of WW domain-containing oxidoreductase.	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of WW domain-containing oxidoreductase.	[9]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of WW domain-containing oxidoreductase.	[12]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of WW domain-containing oxidoreductase.	[13]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of WW domain-containing oxidoreductase.	[14]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of WW domain-containing oxidoreductase.	[15]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of WW domain-containing oxidoreductase.	[16]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of WW domain-containing oxidoreductase.	[17]
Menadione	DMSJDTY	Approved	Menadione affects the expression of WW domain-containing oxidoreductase.	[13]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of WW domain-containing oxidoreductase.	[18]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of WW domain-containing oxidoreductase.	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of WW domain-containing oxidoreductase.	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of WW domain-containing oxidoreductase.	[21]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of WW domain-containing oxidoreductase.	[23]
QUERCITRIN	DM1DH96	Investigative	QUERCITRIN decreases the expression of WW domain-containing oxidoreductase.	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Estradiol	DMUNTE3	Approved	Estradiol decreases the phosphorylation of WW domain-containing oxidoreductase.	[10]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of WW domain-containing oxidoreductase.	[11]
G1	DMTV42K	Phase 1/2	G1 decreases the phosphorylation of WW domain-containing oxidoreductase.	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of WW domain-containing oxidoreductase.	[22]

References

• [1] 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.
• [2] The tumour suppressor gene WWOX is mutated in autosomal recessive cerebellar ataxia with epilepsy and mental retardation. Brain. 2014 Feb;137(Pt 2):411-9. doi: 10.1093/brain/awt338. Epub 2013 Dec 24.
• [3] The supposed tumor suppressor gene WWOX is mutated in an early lethal microcephaly syndrome with epilepsy, growth retardation and retinal degeneration. Orphanet J Rare Dis. 2014 Jan 23;9:12. doi: 10.1186/1750-1172-9-12.
• [4] A multi-exon deletion within WWOX is associated with a 46,XY disorder of sex development. Eur J Hum Genet. 2012 Mar;20(3):348-51. doi: 10.1038/ejhg.2011.204. Epub 2011 Nov 9.
• [5] WWOX-related encephalopathies: delineation of the phenotypical spectrum and emerging genotype-phenotype correlation. J Med Genet. 2015 Jan;52(1):61-70. doi: 10.1136/jmedgenet-2014-102748. Epub 2014 Nov 19.
• [6] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [7] 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.
• [8] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] The G Protein-Coupled Estrogen Receptor Agonist G-1 Inhibits Nuclear Estrogen Receptor Activity and Stimulates Novel Phosphoproteomic Signatures. Toxicol Sci. 2016 Jun;151(2):434-46. doi: 10.1093/toxsci/kfw057. Epub 2016 Mar 29.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [15] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [16] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [17] Inhibition of breast cancer cell growth in vitro and in vivo: effect of restoration of Wwox expression. Clin Cancer Res. 2007 Jan 1;13(1):268-74. doi: 10.1158/1078-0432.CCR-06-2038.
• [18] Cannabidiol Modulates the Immunophenotype and Inhibits the Activation of the Inflammasome in Human Gingival Mesenchymal Stem Cells. Front Physiol. 2016 Nov 24;7:559. doi: 10.3389/fphys.2016.00559. eCollection 2016.
• [19] 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.
• [20] 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.
• [21] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [22] 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.
• [23] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [24] Molecular mechanisms of quercitrin-induced apoptosis in non-small cell lung cancer. Arch Med Res. 2014 Aug;45(6):445-54.
• [25] Population-based in vitro hazard and concentration-response assessment of chemicals: the 1000 genomes high-throughput screening study. Environ Health Perspect. 2015 May;123(5):458-66. doi: 10.1289/ehp.1408775. Epub 2015 Jan 13.