Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT68CH0B)

• DOT Name: Cyclin-O (CCNO)
• Gene Name: CCNO
• Related Disease:
  Primary ciliary dyskinesia 29
  Pulmonary disease
  Adult glioblastoma
  Advanced cancer
  Brain neoplasm
  Chromosomal disorder
  Gastric cancer
  Glioblastoma multiforme
  Glioma
  Malignant glioma
  Mismatch repair cancer syndrome
  Neoplasm
  Stomach cancer
  Primary ciliary dyskinesia 1
  Primary ciliary dyskinesia
  Hydrocephalus
• UniProt ID: CCNO_HUMAN
• Pfam ID: PF02984 ; PF00134
• Sequence:
  MVTPCPTSPSSPAARAGRRDNDQNLRAPVKKSRRPRLRRKQPLHPLNPCPLPGDSGICDL
  FESPSSGSDGAESPSAARGGSPLPGPAQPVAQLDLQTFRDYGQSCYAFRKAQESHFHPRE
  ALARQPQVTAESRCKLLSWLIPVHRQFGLSFESLCLTVNTLDRFLTTTPVAADCFQLLGV
  TSLLIACKQVEVHPPRVKQLLALCCGAFSRQQLCNLECIVLHKLHFTLGAPTISFFLEHF
  THARVEAGQAEASEALEAQALARGVAELSLADYAFTSYSPSLLAICCLALADRMLRVSRP
  VDLRLGDHPEAALEDCMGKLQLLVAINSTSLTHMLPVQICEKCSLPPSSK
• Function: Specifically required for generation of multiciliated cells, possibly by promoting a cell cycle state compatible with centriole amplification and maturation. Acts downstream of MCIDAS to promote mother centriole amplification and maturation in preparation for apical docking.
• Tissue Specificity: Present in respiratory cells (at protein level).

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Primary ciliary dyskinesia 29	DIS3LOEP	Definitive	Autosomal recessive	[1]
Pulmonary disease	DIS6060I	Definitive	Biomarker	[2]
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[3]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[4]
Brain neoplasm	DISY3EKS	Strong	Biomarker	[5]
Chromosomal disorder	DISM5BB5	Strong	Genetic Variation	[6]
Gastric cancer	DISXGOUK	Strong	Biomarker	[4]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[3]
Glioma	DIS5RPEH	Strong	Biomarker	[7]
Malignant glioma	DISFXKOV	Strong	Biomarker	[8]
Mismatch repair cancer syndrome	DISIXHJ2	Strong	Biomarker	[9]
Neoplasm	DISZKGEW	Strong	Biomarker	[10]
Stomach cancer	DISKIJSX	Strong	Biomarker	[4]
Primary ciliary dyskinesia 1	DISPGX6H	moderate	GermlineCausalMutation	[11]
Primary ciliary dyskinesia	DISOBC7V	Supportive	Autosomal dominant	[12]
Hydrocephalus	DISIZUF7	Disputed	Genetic Variation	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	Cyclin-O (CCNO) decreases the response to substance of Arsenic trioxide.	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Cyclin-O (CCNO).	[14]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Cyclin-O (CCNO).	[15]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Cyclin-O (CCNO).	[16]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Cyclin-O (CCNO).	[17]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Cyclin-O (CCNO).	[18]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Cyclin-O (CCNO).	[19]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Cyclin-O (CCNO).	[21]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Cyclin-O (CCNO).	[19]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Cyclin-O (CCNO).	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of Cyclin-O (CCNO).	[20]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Cyclin-O (CCNO).	[23]

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] Genotype and phenotype evaluation of patients with primary ciliary dyskinesia: First results from Turkey.Pediatr Pulmonol. 2020 Feb;55(2):383-393. doi: 10.1002/ppul.24583. Epub 2019 Nov 25.
• [3] Rechallenge with bevacizumab in patients with glioblastoma progressing off therapy.J Neurooncol. 2018 May;138(1):141-145. doi: 10.1007/s11060-018-2780-1. Epub 2018 Jan 31.
• [4] Knockdown of CCNO decreases the tumorigenicity of gastric cancer by inducing apoptosis.Onco Targets Ther. 2018 Oct 26;11:7471-7481. doi: 10.2147/OTT.S176252. eCollection 2018.
• [5] A pilot study of dose-intensified procarbazine, CCNU, vincristine for poor prognosis brain tumors utilizing fibronectin-assisted, retroviral-mediated modification of CD34+ peripheral blood cells with O6-methylguanine DNA methyltransferase.Cancer Gene Ther. 2006 Sep;13(9):886-95. doi: 10.1038/sj.cgt.7700963. Epub 2006 Apr 28.
• [6] Effects of CCNU therapy on human chromosomes.Mutat Res. 1988 Oct;206(2):163-6. doi: 10.1016/0165-1218(88)90155-3.
• [7] (18)F-FET-PET as a biomarker for therapy response in non-contrast enhancing glioma following chemotherapy.J Neurooncol. 2018 Sep;139(3):721-730. doi: 10.1007/s11060-018-2919-0. Epub 2018 Jun 8.
• [8] Procarbazine and CCNU Chemotherapy for Recurrent Glioblastoma with MGMT Promoter Methylation.J Korean Med Sci. 2018 May 10;33(24):e167. doi: 10.3346/jkms.2018.33.e167. eCollection 2018 Jun 11.
• [9] Acquired temozolomide resistance in human glioblastoma cell line U251 is caused by mismatch repair deficiency and can be overcome by lomustine.Clin Transl Oncol. 2018 Apr;20(4):508-516. doi: 10.1007/s12094-017-1743-x. Epub 2017 Aug 20.
• [10] A Case Report of Adult Pineoblastoma Occurring in a Pregnant Woman.Anticancer Res. 2019 May;39(5):2627-2631. doi: 10.21873/anticanres.13386.
• [11] Unexpected genetic heterogeneity for primary ciliary dyskinesia in the Irish Traveller population.Eur J Hum Genet. 2015 Feb;23(2):210-7. doi: 10.1038/ejhg.2014.79. Epub 2014 May 14.
• [12] Mutations in CCNO result in congenital mucociliary clearance disorder with reduced generation of multiple motile cilia. Nat Genet. 2014 Jun;46(6):646-51. doi: 10.1038/ng.2961. Epub 2014 Apr 20.
• [13] Constitutive Cyclin O deficiency results in penetrant hydrocephalus, impaired growth and infertility.Oncotarget. 2017 Oct 12;8(59):99261-99273. doi: 10.18632/oncotarget.21818. eCollection 2017 Nov 21.
• [14] 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.
• [15] 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.
• [16] Retinoic acid receptor alpha amplifications and retinoic acid sensitivity in breast cancers. Clin Breast Cancer. 2013 Oct;13(5):401-8.
• [17] 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.
• [18] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [19] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [20] Epigenetic changes in individuals with arsenicosis. Chem Res Toxicol. 2011 Feb 18;24(2):165-7. doi: 10.1021/tx1004419. Epub 2011 Feb 4.
• [21] Pro-oxidant induced DNA damage in human lymphoblastoid cells: homeostatic mechanisms of genotoxic tolerance. Toxicol Sci. 2012 Aug;128(2):387-97. doi: 10.1093/toxsci/kfs152. Epub 2012 Apr 26.
• [22] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [23] 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.
• [24] The NRF2-mediated oxidative stress response pathway is associated with tumor cell resistance to arsenic trioxide across the NCI-60 panel. BMC Med Genomics. 2010 Aug 13;3:37. doi: 10.1186/1755-8794-3-37.