Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8ZB70U)

• DOT Name: Transcriptional repressor CTCF (CTCF)
• Synonyms: 11-zinc finger protein; CCCTC-binding factor; CTCFL paralog
• Gene Name: CTCF
• Related Disease:
  Bladder cancer
  Childhood acute lymphoblastic leukemia
  Intellectual disability, autosomal dominant 40
  Intellectual disability-feeding difficulties-developmental delay-microcephaly syndrome
  Syndromic intellectual disability
  Urinary bladder cancer
  Urinary bladder neoplasm
  Acute myelogenous leukaemia
  Alzheimer disease
  Carcinoma
  Cardiac failure
  Childhood kidney Wilms tumor
  Colorectal carcinoma
  Congestive heart failure
  Epithelial ovarian cancer
  facioscapulohumeral muscular dystrophy
  Friedreich ataxia 1
  Friedreich's ataxia
  Hepatocellular carcinoma
  Herpes simplex infection
  Intellectual disability
  Kaposi sarcoma
  Movement disorder
  Neuroblastoma
  Neurodevelopmental disorder
  Ovarian cancer
  Ovarian neoplasm
  Primary cutaneous T-cell lymphoma
  Schizophrenia
  Silver-Russell syndrome
  Adult glioblastoma
  Breast neoplasm
  Glioblastoma multiforme
  Invasive breast carcinoma
  Lung cancer
  Lung carcinoma
  Lymphoma
  Pancreatic cancer
  Prostate cancer
  Prostate carcinoma
  T-cell acute lymphoblastic leukaemia
  Non-insulin dependent diabetes
  Acute lymphocytic leukaemia
  Beckwith-Wiedemann syndrome
  Endometrial cancer
  Endometrial carcinoma
  Melanoma
  Nervous system disease
  Prostate neoplasm
  Wilms tumor
• UniProt ID: CTCF_HUMAN
• PDB ID: 1X6H; 2CT1; 5K5H; 5K5I; 5K5J; 5K5L; 5KKQ; 5T00; 5T0U; 5UND; 5YEF; 5YEG; 5YEH; 5YEL; 6QNX; 7W1M; 8SSQ; 8SSR; 8SSS; 8SST; 8SSU
• Pfam ID: PF00096
• Sequence:
  MEGDAVEAIVEESETFIKGKERKTYQRRREGGQEEDACHLPQNQTDGGEVVQDVNSSVQM
  VMMEQLDPTLLQMKTEVMEGTVAPEAEAAVDDTQIITLQVVNMEEQPINIGELQLVQVPV
  PVTVPVATTSVEELQGAYENEVSKEGLAESEPMICHTLPLPEGFQVVKVGANGEVETLEQ
  GELPPQEDPSWQKDPDYQPPAKKTKKTKKSKLRYTEEGKDVDVSVYDFEEEQQEGLLSEV
  NAEKVVGNMKPPKPTKIKKKGVKKTFQCELCSYTCPRRSNLDRHMKSHTDERPHKCHLCG
  RAFRTVTLLRNHLNTHTGTRPHKCPDCDMAFVTSGELVRHRRYKHTHEKPFKCSMCDYAS
  VEVSKLKRHIRSHTGERPFQCSLCSYASRDTYKLKRHMRTHSGEKPYECYICHARFTQSG
  TMKMHILQKHTENVAKFHCPHCDTVIARKSDLGVHLRKQHSYIEQGKKCRYCDAVFHERY
  ALIQHQKSHKNEKRFKCDQCDYACRQERHMIMHKRTHTGEKPYACSHCDKTFRQKQLLDM
  HFKRYHDPNFVPAAFVCSKCGKTFTRRNTMARHADNCAGPDGVEGENGGETKKSKRGRKR
  KMRSKKEDSSDSENAEPDLDDNEDEEEPAVEIEPEPEPQPVTPAPPPAKKRRGRPPGRTN
  QPKQNQPTAIIQVEDQNTGAIENIIVEVKKEPDAEPAEGEEEEAQPAATDAPNGDLTPEM
  ILSMMDR
• Function: Chromatin binding factor that binds to DNA sequence specific sites and regulates the 3D structure of chromatin. Binds together strands of DNA, thus forming chromatin loops, and anchors DNA to cellular structures, such as the nuclear lamina. Defines the boundaries between active and heterochromatic DNA via binding to chromatin insulators, thereby preventing interaction between promoter and nearby enhancers and silencers. Plays a critical role in the epigenetic regulation. Participates in the allele-specific gene expression at the imprinted IGF2/H19 gene locus. On the maternal allele, binding within the H19 imprinting control region (ICR) mediates maternally inherited higher-order chromatin conformation to restrict enhancer access to IGF2. Mediates interchromosomal association between IGF2/H19 and WSB1/NF1 and may direct distant DNA segments to a common transcription factory. Regulates asynchronous replication of IGF2/H19. Plays a critical role in gene silencing over considerable distances in the genome. Preferentially interacts with unmethylated DNA, preventing spreading of CpG methylation and maintaining methylation-free zones. Inversely, binding to target sites is prevented by CpG methylation. Plays an important role in chromatin remodeling. Can dimerize when it is bound to different DNA sequences, mediating long-range chromatin looping. Causes local loss of histone acetylation and gain of histone methylation in the beta-globin locus, without affecting transcription. When bound to chromatin, it provides an anchor point for nucleosomes positioning. Seems to be essential for homologous X-chromosome pairing. May participate with Tsix in establishing a regulatable epigenetic switch for X chromosome inactivation. May play a role in preventing the propagation of stable methylation at the escape genes from X-inactivation. Involved in sister chromatid cohesion. Associates with both centromeres and chromosomal arms during metaphase and required for cohesin localization to CTCF sites. Plays a role in the recruitment of CENPE to the pericentromeric/centromeric regions of the chromosome during mitosis. Acts as a transcriptional repressor binding to promoters of vertebrate MYC gene and BAG1 gene. Also binds to the PLK and PIM1 promoters. Acts as a transcriptional activator of APP. Regulates APOA1/C3/A4/A5 gene cluster and controls MHC class II gene expression. Plays an essential role in oocyte and preimplantation embryo development by activating or repressing transcription. Seems to act as tumor suppressor.
• Tissue Specificity: Ubiquitous. Absent in primary spermatocytes.
• Reactome Pathway: Activation of anterior HOX genes in hindbrain development during early embryogenesis (R-HSA-5617472)

Molecular Interaction Atlas (MIA) of This DOT

50 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bladder cancer	DISUHNM0	Definitive	Posttranslational Modification	[1]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Definitive	Posttranslational Modification	[2]
Intellectual disability, autosomal dominant 40	DISAI0IH	Definitive	Autosomal dominant	[3]
Intellectual disability-feeding difficulties-developmental delay-microcephaly syndrome	DISHBKJT	Definitive	Autosomal dominant	[4]
Syndromic intellectual disability	DISH7SDF	Definitive	Autosomal dominant	[5]
Urinary bladder cancer	DISDV4T7	Definitive	Posttranslational Modification	[1]
Urinary bladder neoplasm	DIS7HACE	Definitive	Posttranslational Modification	[1]
Acute myelogenous leukaemia	DISCSPTN	Strong	Genetic Variation	[6]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[7]
Carcinoma	DISH9F1N	Strong	Biomarker	[8]
Cardiac failure	DISDC067	Strong	Altered Expression	[9]
Childhood kidney Wilms tumor	DIS0NMK3	Strong	Altered Expression	[10]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[11]
Congestive heart failure	DIS32MEA	Strong	Altered Expression	[9]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[12]
facioscapulohumeral muscular dystrophy	DISSE0H0	Strong	Biomarker	[13]
Friedreich ataxia 1	DIS285GE	Strong	Altered Expression	[14]
Friedreich's ataxia	DIS5DV35	Strong	Biomarker	[15]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[16]
Herpes simplex infection	DISL1SAV	Strong	Biomarker	[17]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[18]
Kaposi sarcoma	DISC1H1Z	Strong	Altered Expression	[19]
Movement disorder	DISOJJ2D	Strong	CausalMutation	[20]
Neuroblastoma	DISVZBI4	Strong	Biomarker	[21]
Neurodevelopmental disorder	DIS372XH	Strong	Genetic Variation	[22]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[12]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[12]
Primary cutaneous T-cell lymphoma	DIS35WVW	Strong	Biomarker	[23]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[24]
Silver-Russell syndrome	DISSVJ1D	Strong	Biomarker	[25]
Adult glioblastoma	DISVP4LU	moderate	Altered Expression	[26]
Breast neoplasm	DISNGJLM	moderate	Altered Expression	[27]
Glioblastoma multiforme	DISK8246	moderate	Altered Expression	[26]
Invasive breast carcinoma	DISANYTW	moderate	Altered Expression	[28]
Lung cancer	DISCM4YA	moderate	Biomarker	[29]
Lung carcinoma	DISTR26C	moderate	Biomarker	[29]
Lymphoma	DISN6V4S	moderate	Genetic Variation	[30]
Pancreatic cancer	DISJC981	moderate	Genetic Variation	[31]
Prostate cancer	DISF190Y	moderate	Biomarker	[32]
Prostate carcinoma	DISMJPLE	moderate	Biomarker	[32]
T-cell acute lymphoblastic leukaemia	DIS17AI2	moderate	Biomarker	[33]
Non-insulin dependent diabetes	DISK1O5Z	Disputed	Biomarker	[34]
Acute lymphocytic leukaemia	DISPX75S	Limited	Posttranslational Modification	[2]
Beckwith-Wiedemann syndrome	DISH15GR	Limited	Genetic Variation	[35]
Endometrial cancer	DISW0LMR	Limited	Genetic Variation	[36]
Endometrial carcinoma	DISXR5CY	Limited	Biomarker	[36]
Melanoma	DIS1RRCY	Limited	Biomarker	[37]
Nervous system disease	DISJ7GGT	Limited	Biomarker	[38]
Prostate neoplasm	DISHDKGQ	Limited	Genetic Variation	[39]
Wilms tumor	DISB6T16	Limited	Altered Expression	[40]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Paclitaxel	DMLB81S	Approved	Transcriptional repressor CTCF (CTCF) decreases the response to substance of Paclitaxel.	[47]

3 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 Transcriptional repressor CTCF (CTCF).	[41]
Tretinoin	DM49DUI	Approved	Tretinoin affects the expression of Transcriptional repressor CTCF (CTCF).	[42]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Transcriptional repressor CTCF (CTCF).	[46]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide affects the methylation of Transcriptional repressor CTCF (CTCF).	[43]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Transcriptional repressor CTCF (CTCF).	[44]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Transcriptional repressor CTCF (CTCF).	[45]

References

• [1] Allele-specific methylation analysis on upstream promoter region of H19 by methylation-specific PCR with confronting two-pair primers.Int J Oncol. 2004 Nov;25(5):1273-8.
• [2] Lymphocyte-Specific Chromatin Accessibility Pre-determines Glucocorticoid Resistance in Acute Lymphoblastic Leukemia.Cancer Cell. 2018 Dec 10;34(6):906-921.e8. doi: 10.1016/j.ccell.2018.11.002.
• [3] De novo mutations in the genome organizer CTCF cause intellectual disability. Am J Hum Genet. 2013 Jul 11;93(1):124-31. doi: 10.1016/j.ajhg.2013.05.007. Epub 2013 Jun 6.
• [4] 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.
• [5] 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.
• [6] HOX Loci Focused CRISPR/sgRNA Library Screening Identifying Critical CTCF Boundaries.J Vis Exp. 2019 Mar 31;(145):10.3791/59382. doi: 10.3791/59382.
• [7] Enhancer variants associated with Alzheimer's disease affect gene expression via chromatin looping.BMC Med Genomics. 2019 Sep 9;12(1):128. doi: 10.1186/s12920-019-0574-8.
• [8] CTCF genetic alterations in endometrial carcinoma are pro-tumorigenic.Oncogene. 2017 Jul 20;36(29):4100-4110. doi: 10.1038/onc.2017.25. Epub 2017 Mar 20.
• [9] CTCF inhibits endoplasmic reticulum stress and apoptosis in cardiomyocytes by upregulating RYR2 via inhibiting S100A1.Life Sci. 2020 Feb 1;242:117158. doi: 10.1016/j.lfs.2019.117158. Epub 2019 Dec 16.
• [10] Selective methylation of CpGs at regulatory binding sites controls NNAT expression in Wilms tumors.PLoS One. 2013 Jun 25;8(6):e67605. doi: 10.1371/journal.pone.0067605. Print 2013.
• [11] Identification and validation of colorectal neoplasia-specific methylation biomarkers based on CTCF-binding sites.Oncotarget. 2017 Dec 11;8(69):114183-114194. doi: 10.18632/oncotarget.23172. eCollection 2017 Dec 26.
• [12] CTCF promotes epithelial ovarian cancer metastasis by broadly controlling the expression of metastasis-associated genes.Oncotarget. 2017 Jul 10;8(37):62217-62230. doi: 10.18632/oncotarget.19216. eCollection 2017 Sep 22.
• [13] D4Z4 as a prototype of CTCF and lamins-dependent insulator in human cells.Nucleus. 2010 Jan-Feb;1(1):30-6. doi: 10.4161/nucl.1.1.10799.
• [14] FAST-1 antisense RNA epigenetically alters FXN expression.Sci Rep. 2018 Nov 21;8(1):17217. doi: 10.1038/s41598-018-35639-2.
• [15] Friedreich ataxia patient tissues exhibit increased 5-hydroxymethylcytosine modification and decreased CTCF binding at the FXN locus.PLoS One. 2013 Sep 4;8(9):e74956. doi: 10.1371/journal.pone.0074956. eCollection 2013.
• [16] The effect of CTCF binding sites destruction by CRISPR/Cas9 on transcription of metallothionein gene family in liver hepatocellular carcinoma.Biochem Biophys Res Commun. 2019 Mar 19;510(4):530-538. doi: 10.1016/j.bbrc.2019.01.107. Epub 2019 Feb 7.
• [17] The CCCTC Binding Factor, CTRL2, Modulates Heterochromatin Deposition and the Establishment of Herpes Simplex Virus 1 Latency In Vivo.J Virol. 2019 Jun 14;93(13):e00415-19. doi: 10.1128/JVI.00415-19. Print 2019 Jul 1.
• [18] CTCF: a Swiss-army knife for genome organization and transcription regulation.Essays Biochem. 2019 Apr 23;63(1):157-165. doi: 10.1042/EBC20180069. Print 2019 Apr 23.
• [19] Complex Interactions between Cohesin and CTCF in Regulation of Kaposi's Sarcoma-Associated Herpesvirus Lytic Transcription.J Virol. 2020 Jan 6;94(2):e01279-19. doi: 10.1128/JVI.01279-19. Print 2020 Jan 6.
• [20] Prevalence and architecture of de novo mutations in developmental disorders. Nature. 2017 Feb 23;542(7642):433-438. doi: 10.1038/nature21062. Epub 2017 Jan 25.
• [21] Risk-Associated Long Noncoding RNA FOXD3-AS1 Inhibits Neuroblastoma Progression by Repressing PARP1-Mediated Activation of CTCF.Mol Ther. 2018 Mar 7;26(3):755-773. doi: 10.1016/j.ymthe.2017.12.017. Epub 2017 Dec 22.
• [22] Three additional de novo CTCF mutations in Chinese patients help to define an emerging neurodevelopmental disorder.Am J Med Genet C Semin Med Genet. 2019 Jun;181(2):218-225. doi: 10.1002/ajmg.c.31698. Epub 2019 Mar 20.
• [23] Genomic landscape of cutaneous T cell lymphoma.Nat Genet. 2015 Sep;47(9):1011-9. doi: 10.1038/ng.3356. Epub 2015 Jul 20.
• [24] Functional genomics reveal gene regulatory mechanisms underlying schizophrenia risk.Nat Commun. 2019 Feb 8;10(1):670. doi: 10.1038/s41467-019-08666-4.
• [25] Disruption of genomic neighbourhood at the imprinted IGF2-H19 locus in Beckwith-Wiedemann syndrome and Silver-Russell syndrome.Hum Mol Genet. 2011 Apr 1;20(7):1363-74. doi: 10.1093/hmg/ddr018. Epub 2011 Jan 31.
• [26] Epigenetic silencing of miR-181c by DNA methylation in glioblastoma cell lines.BMC Cancer. 2016 Mar 16;16:226. doi: 10.1186/s12885-016-2273-6.
• [27] BORIS, a paralogue of the transcription factor, CTCF, is aberrantly expressed in breast tumours.Br J Cancer. 2008 Feb 12;98(3):571-9. doi: 10.1038/sj.bjc.6604181. Epub 2008 Jan 15.
• [28] Expression of the transcription factor CTCF in invasive breast cancer: a candidate gene located at 16q22.1.Br J Cancer. 2004 Oct 18;91(8):1591-6. doi: 10.1038/sj.bjc.6602144.
• [29] Tomorrow's genome medicine in lung cancer.Semin Cancer Biol. 2017 Feb;42:39-43. doi: 10.1016/j.semcancer.2016.11.003. Epub 2016 Nov 10.
• [30] Role of chromosomal architecture in germinal center B cells and lymphomagenesis.Curr Opin Hematol. 2019 Jul;26(4):294-302. doi: 10.1097/MOH.0000000000000505.
• [31] A functional variant in the boundary of a topological association domain is associated with pancreatic cancer risk.Mol Carcinog. 2019 Oct;58(10):1855-1862. doi: 10.1002/mc.23077. Epub 2019 Jun 24.
• [32] Expression of CCCTC-binding factor (CTCF) is linked to poor prognosis in prostate cancer.Mol Oncol. 2020 Jan;14(1):129-138. doi: 10.1002/1878-0261.12597. Epub 2019 Nov 29.
• [33] The genomic landscape of pediatric and young adult T-lineage acute lymphoblastic leukemia.Nat Genet. 2017 Aug;49(8):1211-1218. doi: 10.1038/ng.3909. Epub 2017 Jul 3.
• [34] Computational analyses of type 2 diabetes-associated loci identified by genome-wide association studies.J Diabetes. 2017 Apr;9(4):362-377. doi: 10.1111/1753-0407.12421. Epub 2016 Jul 27.
• [35] Is ZFP57 binding to H19/IGF2:IG-DMR affected in Silver-Russell syndrome?.Clin Epigenetics. 2018 Feb 21;10:23. doi: 10.1186/s13148-018-0454-7. eCollection 2018.
• [36] CTCF Expression is Essential for Somatic Cell Viability and Protection Against Cancer.Int J Mol Sci. 2018 Nov 30;19(12):3832. doi: 10.3390/ijms19123832.
• [37] Functional Mutations Form at CTCF-Cohesin Binding Sites in Melanoma Due to Uneven Nucleotide Excision Repair across the Motif.Cell Rep. 2016 Dec 13;17(11):2865-2872. doi: 10.1016/j.celrep.2016.11.055.
• [38] CTCF Governs the Identity and Migration of MGE-Derived Cortical Interneurons.J Neurosci. 2019 Jan 2;39(1):177-192. doi: 10.1523/JNEUROSCI.3496-17.2018. Epub 2018 Oct 30.
• [39] A widely expressed transcription factor with multiple DNA sequence specificity, CTCF, is localized at chromosome segment 16q22.1 within one of the smallest regions of overlap for common deletions in breast and prostate cancers.Genes Chromosomes Cancer. 1998 May;22(1):26-36.
• [40] Frequent hypermethylation of a CTCF binding site influences Wilms tumor 1 expression in Wilms tumors.Oncol Rep. 2014 Apr;31(4):1871-6. doi: 10.3892/or.2014.3019. Epub 2014 Feb 11.
• [41] 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.
• [42] Retinoic acid-induced downmodulation of telomerase activity in human cancer cells. Exp Mol Pathol. 2005 Oct;79(2):108-17.
• [43] Analysis of the transcriptional regulation of cancer-related genes by aberrant DNA methylation of the cis-regulation sites in the promoter region during hepatocyte carcinogenesis caused by arsenic. Oncotarget. 2015 Aug 28;6(25):21493-506. doi: 10.18632/oncotarget.4085.
• [44] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [45] 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.
• [46] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [47] cDNA microarray analysis of isogenic paclitaxel- and doxorubicin-resistant breast tumor cell lines reveals distinct drug-specific genetic signatures of resistance. Breast Cancer Res Treat. 2006 Mar;96(1):17-39. doi: 10.1007/s10549-005-9026-6. Epub 2005 Dec 2.