Details of Drug Off-Target (DOT)

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

• DOT Name: Homeobox protein cut-like 2 (CUX2)
• Synonyms: Homeobox protein cux-2
• Gene Name: CUX2
• Related Disease:
  Bipolar disorder
  Atrial fibrillation
  Autism spectrum disorder
  Developmental and epileptic encephalopathy, 67
  Epilepsy
  High blood pressure
  Intellectual disability
  Multiple sclerosis
  Pervasive developmental disorder
  Stomach cancer
  Thyroid gland papillary carcinoma
  Type-1 diabetes
  Type-1/2 diabetes
  Infantile spasm
  LennoxGastaut syndrome
  Autism
  Gout
  Neurodevelopmental disorder
  Schizophrenia
• UniProt ID: CUX2_HUMAN
• PDB ID: 1WH6; 1WH8; 1X2L
• Pfam ID: PF02376 ; PF00046
• Sequence:
  MAANVGSMFQYWKRFDLRRLQKELNSVASELSARQEESEHSHKHLIELRREFKKNVPEEI
  REMVAPVLKSFQAEVVALSKRSQEAEAAFLSVYKQLIEAPDPVPVFEAARSLDDRLQPPS
  FDPSGQPRRDLHTSWKRNPELLSPKEQREGTSPAGPTLTEGSRLPGIPGKALLTETLLQR
  NEAEKQKGLQEVQITLAARLGEAEEKIKVLHSALKATQAELLELRRKYDEEAASKADEVG
  LIMTNLEKANQRAEAAQREVESLREQLASVNSSIRLACCSPQGPSGDKVNFTLCSGPRLE
  AALASKDREILRLLKDVQHLQSSLQELEEASANQIADLERQLTAKSEAIEKLEEKLQAQS
  DYEEIKTELSILKAMKLASSTCSLPQGMAKPEDSLLIAKEAFFPTQKFLLEKPSLLASPE
  EDPSEDDSIKDSLGTEQSYPSPQQLPPPPGPEDPLSPSPGQPLLGPSLGPDGTRTFSLSP
  FPSLASGERLMMPPAAFKGEAGGLLVFPPAFYGAKPPTAPATPAPGPEPLGGPEPADGGG
  GGAAGPGAEEEQLDTAEIAFQVKEQLLKHNIGQRVFGHYVLGLSQGSVSEILARPKPWRK
  LTVKGKEPFIKMKQFLSDEQNVLALRTIQVRQRGSITPRIRTPETGSDDAIKSILEQAKK
  EIESQKGGEPKTSVAPLSIANGTTPASTSEDAIKSILEQARREMQAQQQALLEMEVAPRG
  RSVPPSPPERPSLATASQNGAPALVKQEEGSGGPAQAPLPVLSPAAFVQSIIRKVKSEIG
  DAGYFDHHWASDRGLLSRPYASVSPSLSSSSSSGYSGQPNGRAWPRGDEAPVPPEDEAAA
  GAEDEPPRTGELKAEGATAEAGARLPYYPAYVPRTLKPTVPPLTPEQYELYMYREVDTLE
  LTRQVKEKLAKNGICQRIFGEKVLGLSQGSVSDMLSRPKPWSKLTQKGREPFIRMQLWLS
  DQLGQAVGQQPGASQASPTEPRSSPSPPPSPTEPEKSSQEPLSLSLESSKENQQPEGRSS
  SSLSGKMYSGSQAPGGIQEIVAMSPELDTYSITKRVKEVLTDNNLGQRLFGESILGLTQG
  SVSDLLSRPKPWHKLSLKGREPFVRMQLWLNDPHNVEKLRDMKKLEKKAYLKRRYGLIST
  GSDSESPATRSECPSPCLQPQDLSLLQIKKPRVVLAPEEKEALRKAYQLEPYPSQQTIEL
  LSFQLNLKTNTVINWFHNYRSRMRREMLVEGTQDEPDLDPSGGPGILPPGHSHPDPTPQS
  PDSETEDQKPTVKELELQEGPEENSTPLTTQDKAQVRIKQEQMEEDAEEEAGSQPQDSGE
  LDKGQGPPKEEHPDPPGNDGLPKVAPGPLLPGGSTPDCPSLHPQQESEAGERLHPDPLSF
  KSASESSRCSLEVSLNSPSAASSPGLMMSVSPVPSSSAPISPSPPGAPPAKVPSASPTAD
  MAGALHPSAKVNPNLQRRHEKMANLNNIIYRVERAANREEALEWEF
• Function: Transcription factor involved in the control of neuronal proliferation and differentiation in the brain. Regulates dendrite development and branching, dendritic spine formation, and synaptogenesis in cortical layers II-III. Binds to DNA in a sequence-specific manner.

Molecular Interaction Atlas (MIA) of This DOT

19 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bipolar disorder	DISAM7J2	Definitive	Biomarker	[1]
Atrial fibrillation	DIS15W6U	Strong	Genetic Variation	[2]
Autism spectrum disorder	DISXK8NV	Strong	Genetic Variation	[3]
Developmental and epileptic encephalopathy, 67	DISQHLQE	Strong	Autosomal dominant	[4]
Epilepsy	DISBB28L	Strong	Genetic Variation	[5]
High blood pressure	DISY2OHH	Strong	Genetic Variation	[6]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[3]
Multiple sclerosis	DISB2WZI	Strong	Altered Expression	[7]
Pervasive developmental disorder	DIS51975	Strong	Genetic Variation	[3]
Stomach cancer	DISKIJSX	Strong	Genetic Variation	[8]
Thyroid gland papillary carcinoma	DIS48YMM	Strong	Biomarker	[9]
Type-1 diabetes	DIS7HLUB	Strong	Genetic Variation	[10]
Type-1/2 diabetes	DISIUHAP	Strong	Genetic Variation	[11]
Infantile spasm	DISZSKDG	Moderate	Autosomal dominant	[12]
LennoxGastaut syndrome	DISOTGO5	Supportive	Autosomal dominant	[5]
Autism	DISV4V1Z	Limited	Biomarker	[13]
Gout	DISHC0U7	Limited	Genetic Variation	[14]
Neurodevelopmental disorder	DIS372XH	Limited	Biomarker	[13]
Schizophrenia	DISSRV2N	Limited	Biomarker	[13]

9 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 Homeobox protein cut-like 2 (CUX2).	[15]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Homeobox protein cut-like 2 (CUX2).	[16]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Homeobox protein cut-like 2 (CUX2).	[17]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Homeobox protein cut-like 2 (CUX2).	[18]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Homeobox protein cut-like 2 (CUX2).	[20]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Homeobox protein cut-like 2 (CUX2).	[21]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Homeobox protein cut-like 2 (CUX2).	[23]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Homeobox protein cut-like 2 (CUX2).	[16]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Homeobox protein cut-like 2 (CUX2).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Homeobox protein cut-like 2 (CUX2).	[19]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Homeobox protein cut-like 2 (CUX2).	[22]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Homeobox protein cut-like 2 (CUX2).	[22]

References

• [1] Linkage disequilibrium mapping of bipolar affective disorder at 12q23-q24 provides evidence for association at CUX2 and FLJ32356.Am J Med Genet B Neuropsychiatr Genet. 2005 Jan 5;132B(1):38-45. doi: 10.1002/ajmg.b.30081.
• [2] Genomic Variants in NEURL, GJA1 and CUX2 Significantly Increase Genetic Susceptibility to Atrial Fibrillation.Sci Rep. 2018 Feb 19;8(1):3297. doi: 10.1038/s41598-018-21611-7.
• [3] A recurrent de novo CUX2 missense variant associated with intellectual disability, seizures, and autism spectrum disorder.Eur J Hum Genet. 2018 Sep;26(9):1388-1391. doi: 10.1038/s41431-018-0184-5. Epub 2018 May 24.
• [4] Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study. Lancet. 2012 Nov 10;380(9854):1674-82. doi: 10.1016/S0140-6736(12)61480-9. Epub 2012 Sep 27.
• [5] The epilepsy phenotypic spectrum associated with a recurrent CUX2 variant. Ann Neurol. 2018 May;83(5):926-934. doi: 10.1002/ana.25222. Epub 2018 Apr 30.
• [6] Interethnic analyses of blood pressure loci in populations of East Asian and European descent.Nat Commun. 2018 Nov 28;9(1):5052. doi: 10.1038/s41467-018-07345-0.
• [7] Neuronal vulnerability and multilineage diversity in multiple sclerosis.Nature. 2019 Sep;573(7772):75-82. doi: 10.1038/s41586-019-1404-z. Epub 2019 Jul 17.
• [8] Genome-wide association study identifies gastric cancer susceptibility loci at 12q24.11-12 and 20q11.21.Cancer Sci. 2018 Dec;109(12):4015-4024. doi: 10.1111/cas.13815. Epub 2018 Oct 31.
• [9] CUX2 functions as an oncogene in papillary thyroid cancer.Onco Targets Ther. 2018 Dec 24;12:217-224. doi: 10.2147/OTT.S185710. eCollection 2019.
• [10] 1000 Genomes-based imputation identifies novel and refined associations for the Wellcome Trust Case Control Consortium phase 1 Data.Eur J Hum Genet. 2012 Jul;20(7):801-5. doi: 10.1038/ejhg.2012.3. Epub 2012 Feb 1.
• [11] Genome-wide association study of clinically defined gout identifies multiple risk loci and its association with clinical subtypes.Ann Rheum Dis. 2016 Apr;75(4):652-9. doi: 10.1136/annrheumdis-2014-206191. Epub 2015 Feb 2.
• [12] 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.
• [13] Cux2 expression regulated by Lhx2 in the upper layer neurons of the developing cortex.Biochem Biophys Res Commun. 2020 Jan 22;521(4):874-879. doi: 10.1016/j.bbrc.2019.11.004. Epub 2019 Nov 8.
• [14] GWAS of clinically defined gout and subtypes identifies multiple susceptibility loci that include urate transporter genes.Ann Rheum Dis. 2017 May;76(5):869-877. doi: 10.1136/annrheumdis-2016-209632. Epub 2016 Nov 29.
• [15] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [16] 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.
• [17] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [18] 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.
• [19] 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.
• [20] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [21] Coordinate up-regulation of TMEM97 and cholesterol biosynthesis genes in normal ovarian surface epithelial cells treated with progesterone: implications for pathogenesis of ovarian cancer. BMC Cancer. 2007 Dec 11;7:223.
• [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] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [24] 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.