Details of Drug Off-Target (DOT)

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

• DOT Name: Protein capicua homolog (CIC)
• Gene Name: CIC
• Related Disease:
  Intellectual disability, autosomal dominant 45
  Myotonia congenita, autosomal dominant
  Adult glioblastoma
  Advanced cancer
  Angiosarcoma
  Astrocytoma
  Attention deficit hyperactivity disorder
  Autism spectrum disorder
  Autoimmune disease
  Breast cancer
  Breast carcinoma
  Cerebral folate deficiency
  Colorectal carcinoma
  Epilepsy
  Epithelial ovarian cancer
  Glioblastoma multiforme
  Glioma
  Hepatocellular carcinoma
  Intellectual disability
  Medulloblastoma
  Multiple sclerosis
  Neuroblastoma
  Ovarian cancer
  Ovarian neoplasm
  Rhabdomyosarcoma
  Small-cell lung cancer
  Soft tissue neoplasm
  Soft tissue sarcoma
  Systemic lupus erythematosus
  Ewing sarcoma/peripheral primitive neuroectodermal tumor
  Gastrointestinal stromal tumour
  Melanoma
  Stomach cancer
  Autosomal dominant non-syndromic intellectual disability
  Autosomal dominant cerebellar ataxia type II
  Desmoplastic small round cell tumor
  Malignant rhabdoid tumour
  Rheumatoid arthritis
  Spinocerebellar ataxia type 1
  Spinocerebellar ataxia type 2
  Spinocerebellar ataxia type 5
  Spinocerebellar ataxia type 6
• UniProt ID: CIC_HUMAN
• PDB ID: 2M41; 4J2J; 4J2L; 6JRP; 6KZG; 6KZH
• Pfam ID: PF00505
• Sequence:
  MYSAHRPLMPASSAASRGLGMFVWTNVEPRSVAVFPWHSLVPFLAPSQPDPSVQPSEAQQ
  PASHPVASNQSKEPAESAAVAHERPPGGTGSADPERPPGATCPESPGPGPPHPLGVVESG
  KGPPPTTEEEASGPPGEPRLDSETESDHDDAFLSIMSPEIQLPLPPGKRRTQSLSALPKE
  RDSSSEKDGRSPNKREKDHIRRPMNAFMIFSKRHRALVHQRHPNQDNRTVSKILGEWWYA
  LGPKEKQKYHDLAFQVKEAHFKAHPDWKWCNKDRKKSSSEAKPTSLGLAGGHKETRERSM
  SETGTAAAPGVSSELLSVAAQTLLSSDTKAPGSSSCGAERLHTVGGPGSARPRAFSHSGV
  HSLDGGEVDSQALQELTQMVSGPASYSGPKPSTQYGAPGPFAAPGEGGALAATGRPPLLP
  TRASRSQRAASEDMTSDEERMVICEEEGDDDVIADDGFGTTDIDLKCKERVTDSESGDSS
  GEDPEGNKGFGRKVFSPVIRSSFTHCRPPLDPEPPGPPDPPVAFGKGYGSAPSSSASSPA
  SSSASAATSFSLGSGTFKAQESGQGSTAGPLRPPPPGAGGPATPSKATRFLPMDPATFRR
  KRPESVGGLEPPGPSVIAAPPSGGGNILQTLVLPPNKEEQEGGGARVPSAPAPSLAYGAP
  AAPLSRPAATMVTNVVRPVSSTPVPIASKPFPTSGRAEASPNDTAGARTEMGTGSRVPGG
  SPLGVSLVYSDKKSAAATSPAPHLVAGPLLGTVGKAPATVTNLLVGTPGYGAPAPPAVQF
  IAQGAPGGGTTAGSGAGAGSGPNGPVPLGILQPGALGKAGGITQVQYILPTLPQQLQVAP
  APAPAPGTKAAAPSGPAPTTSIRFTLPPGTSTNGKVLAATAPTPGIPILQSVPSAPPPKA
  QSVSPVQAPPPGGSAQLLPGKVLVPLAAPSMSVRGGGAGQPLPLVSPPFSVPVQNGAQPP
  SKIIQLTPVPVSTPSGLVPPLSPATLPGPTSQPQKVLLPSSTRITYVQSAGGHALPLGTS
  PASSQAGTVTSYGPTSSVALGFTSLGPSGPAFVQPLLSAGQAPLLAPGQVGVSPVPSPQL
  PPACAAPGGPVITAFYSGSPAPTSSAPLAQPSQAPPSLVYTVATSTTPPAATILPKGPPA
  PATATPAPTSPFPSATAGSMTYSLVAPKAQRPSPKAPQKVKAAIASIPVGSFEAGASGRP
  GPAPRQPLEPGPVREPTAPESELEGQPTPPAPPPLPETWTPTARSSPPLPPPAEERTSAK
  GPETMASKFPSSSSDWRVPGQGLENRGEPPTPPSPAPAPAVAPGGSSESSSGRAAGDTPE
  RKEAAGTGKKVKVRPPPLKKTFDSVDNRVLSEVDFEERFAELPEFRPEEVLPSPTLQSLA
  TSPRAILGSYRKKRKNSTDLDSAPEDPTSPKRKMRRRSSCSSEPNTPKSAKCEGDIFTFD
  RTGTEAEDVLGELEYDKVPYSSLRRTLDQRRALVMQLFQDHGFFPSAQATAAFQARYADI
  FPSKVCLQLKIREVRQKIMQAATPTEQPPGAEAPLPVPPPTGTAAAPAPTPSPAGGPDPT
  SPSSDSGTAQAAPPLPPPPESGPGQPGWEGAPQPSPPPPGPSTAATGR
• Function: Transcriptional repressor which plays a role in development of the central nervous system (CNS). In concert with ATXN1 and ATXN1L, involved in brain development.
• Tissue Specificity: Expressed in fetal brain.
• KEGG Pathway: Spinocerebellar ataxia (hsa05017)

Molecular Interaction Atlas (MIA) of This DOT

42 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Intellectual disability, autosomal dominant 45	DISAEI7N	Definitive	Autosomal dominant	[1]
Myotonia congenita, autosomal dominant	DISAC9U9	Definitive	Genetic Variation	[2]
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[3]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[4]
Angiosarcoma	DISIYS9W	Strong	Biomarker	[5]
Astrocytoma	DISL3V18	Strong	Genetic Variation	[6]
Attention deficit hyperactivity disorder	DISL8MX9	Strong	Biomarker	[1]
Autism spectrum disorder	DISXK8NV	Strong	Biomarker	[1]
Autoimmune disease	DISORMTM	Strong	Biomarker	[7]
Breast cancer	DIS7DPX1	Strong	Biomarker	[8]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[8]
Cerebral folate deficiency	DISCLJJ3	Strong	Autosomal dominant	[9]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[10]
Epilepsy	DISBB28L	Strong	Altered Expression	[11]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[12]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[3]
Glioma	DIS5RPEH	Strong	Altered Expression	[13]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[14]
Intellectual disability	DISMBNXP	Strong	Altered Expression	[11]
Medulloblastoma	DISZD2ZL	Strong	Genetic Variation	[15]
Multiple sclerosis	DISB2WZI	Strong	Biomarker	[16]
Neuroblastoma	DISVZBI4	Strong	Genetic Variation	[17]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[12]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[12]
Rhabdomyosarcoma	DISNR7MS	Strong	Biomarker	[18]
Small-cell lung cancer	DISK3LZD	Strong	Genetic Variation	[17]
Soft tissue neoplasm	DISP2OHE	Strong	Biomarker	[19]
Soft tissue sarcoma	DISSN8XB	Strong	Genetic Variation	[20]
Systemic lupus erythematosus	DISI1SZ7	Strong	Biomarker	[21]
Ewing sarcoma/peripheral primitive neuroectodermal tumor	DISD4VQC	moderate	Biomarker	[22]
Gastrointestinal stromal tumour	DIS6TJYS	moderate	Altered Expression	[23]
Melanoma	DIS1RRCY	moderate	Altered Expression	[23]
Stomach cancer	DISKIJSX	moderate	Genetic Variation	[24]
Autosomal dominant non-syndromic intellectual disability	DISD6L06	Supportive	Autosomal dominant	[1]
Autosomal dominant cerebellar ataxia type II	DIS0PM39	Limited	Biomarker	[25]
Desmoplastic small round cell tumor	DISLI2ME	Limited	Genetic Variation	[17]
Malignant rhabdoid tumour	DIS46HZU	Limited	Genetic Variation	[17]
Rheumatoid arthritis	DISTSB4J	Limited	Biomarker	[26]
Spinocerebellar ataxia type 1	DISF7BO2	Limited	Biomarker	[25]
Spinocerebellar ataxia type 2	DISF7WDI	Limited	Biomarker	[25]
Spinocerebellar ataxia type 5	DISPYXJ0	Limited	Biomarker	[25]
Spinocerebellar ataxia type 6	DISH7224	Limited	Biomarker	[25]

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 Protein capicua homolog (CIC).	[27]
Quercetin	DM3NC4M	Approved	Quercetin increases the phosphorylation of Protein capicua homolog (CIC).	[30]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Protein capicua homolog (CIC).	[32]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Protein capicua homolog (CIC).	[30]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Protein capicua homolog (CIC).	[28]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Protein capicua homolog (CIC).	[29]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Protein capicua homolog (CIC).	[31]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Protein capicua homolog (CIC).	[33]

References

• [1] Disruption of the ATXN1-CIC complex causes a spectrum of neurobehavioral phenotypes in mice and humans. Nat Genet. 2017 Apr;49(4):527-536. doi: 10.1038/ng.3808. Epub 2017 Mar 13.
• [2] Novel mutations at carboxyl terminus of CIC-1 channel in myotonia congenita.Acta Neurol Scand. 2006 May;113(5):342-6. doi: 10.1111/j.1600-0404.2006.00589.x.
• [3] CIC protein instability contributes to tumorigenesis in glioblastoma.Nat Commun. 2019 Feb 8;10(1):661. doi: 10.1038/s41467-018-08087-9.
• [4] Interplay between heat shock proteins, inflammation and cancer: a potential cancer therapeutic target.Am J Cancer Res. 2019 Feb 1;9(2):242-249. eCollection 2019.
• [5] ETV transcriptional upregulation is more reliable than RNA sequencing algorithms and FISH in diagnosing round cell sarcomas with CIC gene rearrangements.Genes Chromosomes Cancer. 2017 Jun;56(6):501-510. doi: 10.1002/gcc.22454. Epub 2017 Mar 31.
• [6] Molecular Diagnostics of Gliomas Using Next Generation Sequencing of a Glioma-Tailored Gene Panel.Brain Pathol. 2017 Mar;27(2):146-159. doi: 10.1111/bpa.12367. Epub 2016 Apr 19.
• [7] Capicua deficiency induces autoimmunity and promotes follicular helper T cell differentiation via derepression of ETV5.Nat Commun. 2017 Jul 12;8:16037. doi: 10.1038/ncomms16037.
• [8] Subtype-Based Prognostic Analysis of Cell-in-Cell Structures in Early Breast Cancer.Front Oncol. 2019 Sep 20;9:895. doi: 10.3389/fonc.2019.00895. eCollection 2019.
• [9] CIC de novo loss of function variants contribute to cerebral folate deficiency by downregulating FOLR1 expression. J Med Genet. 2021 Jul;58(7):484-494. doi: 10.1136/jmedgenet-2020-106987. Epub 2020 Aug 20.
• [10] Heat shock protein DNAJB8 is a novel target for immunotherapy of colon cancer-initiating cells.Cancer Sci. 2014 Apr;105(4):389-95. doi: 10.1111/cas.12362. Epub 2014 Feb 24.
• [11] De novo and inherited mutations in the X-linked gene CLCN4 are associated with syndromic intellectual disability and behavior and seizure disorders in males and females.Mol Psychiatry. 2018 Feb;23(2):222-230. doi: 10.1038/mp.2016.135. Epub 2016 Aug 23.
• [12] MiR-1307 influences the chemotherapeutic sensitivity in ovarian cancer cells through the regulation of the CIC transcriptional repressor.Pathol Res Pract. 2019 Oct;215(10):152606. doi: 10.1016/j.prp.2019.152606. Epub 2019 Aug 19.
• [13] CIC inactivating mutations identify aggressive subset of 1p19q codeleted gliomas.Ann Neurol. 2015 Sep;78(3):355-74. doi: 10.1002/ana.24443. Epub 2015 Jul 27.
• [14] Annexin A3 as a potential target for immunotherapy of liver cancer stem-like cells.Stem Cells. 2015 Feb;33(2):354-66. doi: 10.1002/stem.1850.
• [15] CIC and FUBP1 mutations in oligodendrogliomas, oligoastrocytomas and astrocytomas.Acta Neuropathol. 2012 Jun;123(6):853-60. doi: 10.1007/s00401-012-0993-5. Epub 2012 May 17.
• [16] The cost of a catheter: An environmental perspective on single use clean intermittent catheterization.Neurourol Urodyn. 2018 Sep;37(7):2204-2208. doi: 10.1002/nau.23562. Epub 2018 Aug 14.
• [17] Review with novel markers facilitates precise categorization of 41 cases of diagnostically challenging, "undifferentiated small round cell tumors". A clinicopathologic, immunophenotypic and molecular analysis.Ann Diagn Pathol. 2018 Jun;34:1-12. doi: 10.1016/j.anndiagpath.2017.11.011. Epub 2017 Nov 29.
• [18] CD133 marks a myogenically primitive subpopulation in rhabdomyosarcoma cell lines that are relatively chemoresistant but sensitive to mutant HSV.Pediatr Blood Cancer. 2013 Jan;60(1):45-52. doi: 10.1002/pbc.24117. Epub 2012 Mar 9.
• [19] Distinct transcriptional signature and immunoprofile of CIC-DUX4 fusion-positive round cell tumors compared to EWSR1-rearranged Ewing sarcomas: further evidence toward distinct pathologic entities.Genes Chromosomes Cancer. 2014 Jul;53(7):622-33. doi: 10.1002/gcc.22172. Epub 2014 Apr 10.
• [20] DNA methylation profiling distinguishes Ewing-like sarcoma with EWSR1-NFATc2 fusion from Ewing sarcoma.J Cancer Res Clin Oncol. 2019 May;145(5):1273-1281. doi: 10.1007/s00432-019-02895-2. Epub 2019 Mar 20.
• [21] Association of leukocyte CR1 gene transcription with the disease severity and renal involvement in systemic lupus erythematosus.Lupus. 2005;14(4):273-9. doi: 10.1191/0961203305lu2074oa.
• [22] Immunohistochemical analysis of NKX2.2, ETV4, and BCOR in a large series of genetically confirmed Ewing sarcoma family of tumors.Pathol Res Pract. 2017 Sep;213(9):1048-1053. doi: 10.1016/j.prp.2017.08.002. Epub 2017 Aug 25.
• [23] Downregulation of CIC does not associate with overexpression of ETV1 or MAP kinase pathway activation in gastrointestinal stromal tumors.Cancer Invest. 2014 Aug;32(7):363-7. doi: 10.3109/07357907.2014.919304. Epub 2014 Jun 4.
• [24] A double-edged sword: The world according to Capicua in cancer.Cancer Sci. 2017 Dec;108(12):2319-2325. doi: 10.1111/cas.13413. Epub 2017 Oct 25.
• [25] Opposing effects of polyglutamine expansion on native protein complexes contribute to SCA1.Nature. 2008 Apr 10;452(7188):713-8. doi: 10.1038/nature06731. Epub 2008 Mar 12.
• [26] Diagnostic value of glucose-6-phosphate isomerase in rheumatoid arthritis.Clin Chim Acta. 2010 Dec 14;411(23-24):2049-53. doi: 10.1016/j.cca.2010.08.043. Epub 2010 Sep 15.
• [27] 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.
• [28] 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.
• [29] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [30] 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.
• [31] 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.
• [32] 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.
• [33] 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.