Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTL10OY6)

• DOT Name: Dual specificity protein phosphatase CDC14A (CDC14A)
• Synonyms: EC 3.1.3.16; EC 3.1.3.48; CDC14 cell division cycle 14 homolog A
• Gene Name: CDC14A
• Related Disease:
  Deafness
  Mycoses
  Advanced cancer
  Autosomal recessive nonsyndromic hearing loss 32
  Breast cancer
  Breast carcinoma
  Colorectal carcinoma
  Dental caries
  Hearing impairment and infertile male syndrome
  Male infertility
  Obsolete autosomal recessive nonsyndromic deafness 105
  Oligospermia
  Hearing loss, autosomal recessive
  Gastric cancer
  Nonsyndromic genetic hearing loss
• UniProt ID: CC14A_HUMAN
• EC Number: 3.1.3.16; 3.1.3.48
• Pfam ID: PF00782 ; PF14671
• Sequence:
  MAAESGELIGACEFMKDRLYFATLRNRPKSTVNTHYFSIDEELVYENFYADFGPLNLAMV
  YRYCCKLNKKLKSYSLSRKKIVHYTCFDQRKRANAAFLIGAYAVIYLKKTPEEAYRALLS
  GSNPPYLPFRDASFGNCTYNLTILDCLQGIRKGLQHGFFDFETFDVDEYEHYERVENGDF
  NWIVPGKFLAFSGPHPKSKIENGYPLHAPEAYFPYFKKHNVTAVVRLNKKIYEAKRFTDA
  GFEHYDLFFIDGSTPSDNIVRRFLNICENTEGAIAVHCKAGLGRTGTLIACYVMKHYRFT
  HAEIIAWIRICRPGSIIGPQQHFLEEKQASLWVQGDIFRSKLKNRPSSEGSINKILSGLD
  DMSIGGNLSKTQNMERFGEDNLEDDDVEMKNGITQGDKLRALKSQRQPRTSPSCAFRSDD
  TKGHPRAVSQPFRLSSSLQGSAVTLKTSKMALSPSATAKRINRTSLSSGATVRSFSINSR
  LASSLGNLNAATDDPENKKTSSSSKAGFTASPFTNLLNGSSQPTTRNYPELNNNQYNRSS
  NSNGGNLNSPPGPHSAKTEEHTTILRPSYTGLSSSSARFLSRSIPSLQSEYVHY
• Function: Dual-specificity phosphatase. Required for centrosome separation and productive cytokinesis during cell division. Dephosphorylates SIRT2 around early anaphase. May dephosphorylate the APC subunit FZR1/CDH1, thereby promoting APC-FZR1 dependent degradation of mitotic cyclins and subsequent exit from mitosis. Required for normal hearing.
• KEGG Pathway: Cell cycle (hsa04110)
• Reactome Pathway:
  MAPK6/MAPK4 signaling (R-HSA-5687128)
  Conversion from APC/C (R-HSA-176407)

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Deafness	DISKCLH4	Definitive	Genetic Variation	[1]
Mycoses	DIS9K7PB	Definitive	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[3]
Autosomal recessive nonsyndromic hearing loss 32	DISNYNXY	Strong	Autosomal recessive	[4]
Breast cancer	DIS7DPX1	Strong	Biomarker	[5]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[6]
Colorectal carcinoma	DIS5PYL0	Strong	Genetic Variation	[3]
Dental caries	DISRBCMD	Strong	Genetic Variation	[1]
Hearing impairment and infertile male syndrome	DIS6I3UN	Strong	Autosomal recessive	[7]
Male infertility	DISY3YZZ	Strong	Biomarker	[4]
Obsolete autosomal recessive nonsyndromic deafness 105	DIS1EOZ3	Strong	Autosomal recessive	[8]
Oligospermia	DIS6YJF3	Strong	Biomarker	[4]
Hearing loss, autosomal recessive	DIS8G9R9	Supportive	Autosomal recessive	[9]
Gastric cancer	DISXGOUK	Limited	Genetic Variation	[3]
Nonsyndromic genetic hearing loss	DISZX61P	Limited	Autosomal recessive	[7]

12 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 Dual specificity protein phosphatase CDC14A (CDC14A).	[10]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Dual specificity protein phosphatase CDC14A (CDC14A).	[11]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Dual specificity protein phosphatase CDC14A (CDC14A).	[12]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Dual specificity protein phosphatase CDC14A (CDC14A).	[13]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Dual specificity protein phosphatase CDC14A (CDC14A).	[14]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Dual specificity protein phosphatase CDC14A (CDC14A).	[16]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Dual specificity protein phosphatase CDC14A (CDC14A).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Dual specificity protein phosphatase CDC14A (CDC14A).	[18]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Dual specificity protein phosphatase CDC14A (CDC14A).	[19]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Dual specificity protein phosphatase CDC14A (CDC14A).	[20]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Dual specificity protein phosphatase CDC14A (CDC14A).	[21]
GW-3965	DMG60ET	Investigative	GW-3965 increases the expression of Dual specificity protein phosphatase CDC14A (CDC14A).	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Dual specificity protein phosphatase CDC14A (CDC14A).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Dual specificity protein phosphatase CDC14A (CDC14A).	[15]

References

• [1] Role of estrogen related receptor beta (ESRRB) in DFN35B hearing impairment and dental decay.BMC Med Genet. 2014 Jul 15;15:81. doi: 10.1186/1471-2350-15-81.
• [2] The Aspergillus flavus Phosphatase CDC14 Regulates Development, Aflatoxin Biosynthesis and Pathogenicity.Front Cell Infect Microbiol. 2018 May 7;8:141. doi: 10.3389/fcimb.2018.00141. eCollection 2018.
• [3] Mutational analysis of mononucleotide repeats in dual specificity tyrosine phosphatase genes in gastric and colon carcinomas with microsatellite instability.APMIS. 2010 May;118(5):389-93. doi: 10.1111/j.1600-0463.2010.02612.x.
• [4] CDC14A phosphatase is essential for hearing and male fertility in mouse and human. Hum Mol Genet. 2018 Mar 1;27(5):780-798. doi: 10.1093/hmg/ddx440.
• [5] Evaluation of associations between common variation in mitotic regulatory pathways and risk of overall and high grade breast cancer.Breast Cancer Res Treat. 2011 Sep;129(2):617-22. doi: 10.1007/s10549-011-1587-y. Epub 2011 May 24.
• [6] Association analysis identifies 65 new breast cancer risk loci.Nature. 2017 Nov 2;551(7678):92-94. doi: 10.1038/nature24284. Epub 2017 Oct 23.
• [7] 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.
• [8] [Obligatory education...]. Pieleg Polozna. 1978;(10):9-10.
• [9] Mutations in CDC14A, Encoding a Protein Phosphatase Involved in Hair Cell Ciliogenesis, Cause Autosomal-Recessive Severe to Profound Deafness. Am J Hum Genet. 2016 Jun 2;98(6):1266-1270. doi: 10.1016/j.ajhg.2016.04.015.
• [10] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [11] 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.
• [12] Quercetin potentiates apoptosis by inhibiting nuclear factor-kappaB signaling in H460 lung cancer cells. Biol Pharm Bull. 2013;36(6):944-51. doi: 10.1248/bpb.b12-01004.
• [13] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [14] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [15] 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.
• [16] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [17] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [18] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [19] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [20] 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.
• [21] 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.
• [22] System analysis of cross-talk between nuclear receptors reveals an opposite regulation of the cell cycle by LXR and FXR in human HepaRG liver cells. PLoS One. 2019 Aug 22;14(8):e0220894. doi: 10.1371/journal.pone.0220894. eCollection 2019.