Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTTAI5S2)

• DOT Name: Centrosomal protein of 78 kDa (CEP78)
• Synonyms: Cep78
• Gene Name: CEP78
• Related Disease:
  Advanced cancer
  Blindness
  Colorectal carcinoma
  Cone-rod dystrophy and hearing loss
  Cone-rod dystrophy and hearing loss 1
  Differentiated thyroid carcinoma
  Goiter
  Neoplasm
  Retinitis pigmentosa
  Usher syndrome
  Usher syndrome type 3
• UniProt ID: CEP78_HUMAN
• Pfam ID: PF13516
• Sequence:
  MIDSVKLRRDSAADFFSHYEYLCALQNSVPLPAVRACLREGVLDFNADRLRGVDWAPLLS
  TLKINKDLPLVSIKSFFQPWLGDTGSDMNKFCRSRVPAIRYKDVTFQLCKALKGCLSISS
  VLKNLELNGLILRERDLTILAKGLNKSASLVHLSLANCPIGDGGLEIICQGIKSSITLKT
  VNFTGCNLTWQGADHMAKILKYQTMRRHEETWAESLRYRRPDLDCMAGLRRITLNCNTLI
  GDLGACAFADSLSEDLWLRALDLQQCGLTNEGAKALLEALETNTTLVVLDIRKNPLIDHS
  MMKAVIKKVLQNGRSAKSEYQWITSPSVKEPSKTAKQKRRTIILGSGHKGKATIRIGLAT
  KKPVSSGRKHSLGKEYYAPAPLPPGVSGFLPWRTAERAKRHRGFPLIKTRDICNQLQQPG
  FPVTVTVESPSSSEVEEVDDSSESVHEVPEKTSIEQEALQEKLEECLKQLKEERVIRLKV
  DKRVSELEHENAQLRNINFSLSEALHAQSLTNMILDDEGVLGSIENSFQKFHAFLDLLKD
  AGLGQLATMAGIDQSDFQLLGHPQMTSTVSNPPKEEKKALEDEKPEPKQNALGQMQNIQF
  QKITGDARIPLPLDSFPVPVSTPEGLGTSSNNLGVPATEQRQESFEGFIARMCSPSPDAT
  SGTGSQRKEEELSRNSRSSSEKKTKTESH
• Function: May be required for efficient PLK4 centrosomal localization and PLK4-induced overduplication of centrioles. May play a role in cilium biogenesis.
• Tissue Specificity: Widely expressed . Expressed in different retinal cell types with higher expression in cone compared to rod cells (at protein level) .
• Reactome Pathway:
  Loss of Nlp from mitotic centrosomes (R-HSA-380259)
  Recruitment of mitotic centrosome proteins and complexes (R-HSA-380270)
  Loss of proteins required for interphase microtubule organization from the centrosome (R-HSA-380284)
  Recruitment of NuMA to mitotic centrosomes (R-HSA-380320)
  Anchoring of the basal body to the plasma membrane (R-HSA-5620912)
  AURKA Activation by TPX2 (R-HSA-8854518)
  Regulation of PLK1 Activity at G2/M Transition (R-HSA-2565942)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Blindness	DISTIM10	Strong	Genetic Variation	[2]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[1]
Cone-rod dystrophy and hearing loss	DISZIE9F	Strong	Autosomal recessive	[3]
Cone-rod dystrophy and hearing loss 1	DISBJ79A	Strong	Autosomal recessive	[4]
Differentiated thyroid carcinoma	DIS1V20Y	Strong	Altered Expression	[5]
Goiter	DISLCGI6	Strong	Altered Expression	[5]
Neoplasm	DISZKGEW	Strong	Altered Expression	[1]
Retinitis pigmentosa	DISCGPY8	Strong	Genetic Variation	[2]
Usher syndrome	DIS9YIS7	Strong	Genetic Variation	[2]
Usher syndrome type 3	DISRAL84	Supportive	Autosomal recessive	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Centrosomal protein of 78 kDa (CEP78).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Centrosomal protein of 78 kDa (CEP78).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Centrosomal protein of 78 kDa (CEP78).	[9]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Centrosomal protein of 78 kDa (CEP78).	[10]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Centrosomal protein of 78 kDa (CEP78).	[11]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Centrosomal protein of 78 kDa (CEP78).	[11]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Centrosomal protein of 78 kDa (CEP78).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Centrosomal protein of 78 kDa (CEP78).	[15]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Centrosomal protein of 78 kDa (CEP78).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Centrosomal protein of 78 kDa (CEP78).	[13]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Centrosomal protein of 78 kDa (CEP78).	[14]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Centrosomal protein of 78 kDa (CEP78).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Centrosomal protein of 78 kDa (CEP78).	[17]

References

• [1] Low expression of centrosomal protein 78 (CEP78) is associated with poor prognosis of colorectal cancer patients.Chin J Cancer. 2016 Jun 29;35(1):62. doi: 10.1186/s40880-016-0121-3.
• [2] Mutations in CEP78 Cause Cone-Rod Dystrophy and Hearing Loss Associated with Primary-Cilia Defects. Am J Hum Genet. 2016 Sep 1;99(3):770-776. doi: 10.1016/j.ajhg.2016.07.009.
• [3] 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.
• [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] Significance of CEP78 and WDR62 gene expressions in differentiated thyroid carcinoma: Possible predictors of lateral lymph node metastasis.Asia Pac J Clin Oncol. 2019 Oct;15(5):e154-e161. doi: 10.1111/ajco.13143. Epub 2019 Mar 18.
• [6] CEP78 is mutated in a distinct type of Usher syndrome. J Med Genet. 2017 Mar;54(3):190-195. doi: 10.1136/jmedgenet-2016-104166. Epub 2016 Sep 14.
• [7] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [8] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [9] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [10] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [11] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [12] Cannabidiol Activates Neuronal Precursor Genes in Human Gingival Mesenchymal Stromal Cells. J Cell Biochem. 2017 Jun;118(6):1531-1546. doi: 10.1002/jcb.25815. Epub 2016 Dec 29.
• [13] 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.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] 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.
• [18] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.