Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6CMCS0)

• DOT Name: CCR4-NOT transcription complex subunit 8 (CNOT8)
• Synonyms: EC 3.1.13.4; CAF1-like protein; CALIFp; CAF2; CCR4-associated factor 8; Caf1b
• Gene Name: CNOT8
• Related Disease:
  Adolescent meningitis
  Breast cancer
  Breast carcinoma
  Carcinoma
  Prostate cancer
  Prostate carcinoma
  Renal cell carcinoma
  Squamous cell carcinoma
  Systemic lupus erythematosus
  Advanced cancer
  Bacterial infection
  Laryngeal carcinoma
  Laryngeal disorder
  Laryngeal squamous cell carcinoma
  Neoplasm
  Cutaneous melanoma
  facioscapulohumeral muscular dystrophy
• UniProt ID: CNOT8_HUMAN
• EC Number: 3.1.13.4
• Pfam ID: PF04857
• Sequence:
  MPAALVENSQVICEVWASNLEEEMRKIREIVLSYSYIAMDTEFPGVVVRPIGEFRSSIDY
  QYQLLRCNVDLLKIIQLGLTFTNEKGEYPSGINTWQFNFKFNLTEDMYSQDSIDLLANSG
  LQFQKHEEEGIDTLHFAELLMTSGVVLCDNVKWLSFHSGYDFGYMVKLLTDSRLPEEEHE
  FFHILNLFFPSIYDVKYLMKSCKNLKGGLQEVADQLDLQRIGRQHQAGSDSLLTGMAFFR
  MKELFFEDSIDDAKYCGRLYGLGTGVAQKQNEDVDSAQEKMSILAIINNMQQ
• Function: Has 3'-5' poly(A) exoribonuclease activity for synthetic poly(A) RNA substrate. Its function seems to be partially redundant with that of CNOT7. Catalytic component of the CCR4-NOT complex which is linked to various cellular processes including bulk mRNA degradation, miRNA-mediated repression, translational repression during translational initiation and general transcription regulation. During miRNA-mediated repression the complex seems also to act as translational repressor during translational initiation. Additional complex functions may be a consequence of its influence on mRNA expression. Associates with members of the BTG family such as TOB1 and BTG2 and is required for their anti-proliferative activity.
• KEGG Pathway: R. degradation (hsa03018)
• Reactome Pathway:
  TP53 regulates transcription of additional cell cycle genes whose exact role in the p53 pathway remain uncertain (R-HSA-6804115)
  M-decay (R-HSA-9820841)
  Deadenylation of mRNA (R-HSA-429947)

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adolescent meningitis	DISYHNYB	Definitive	Biomarker	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[2]
Carcinoma	DISH9F1N	Strong	Biomarker	[2]
Prostate cancer	DISF190Y	Strong	Biomarker	[3]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[3]
Renal cell carcinoma	DISQZ2X8	Strong	Altered Expression	[2]
Squamous cell carcinoma	DISQVIFL	Strong	Biomarker	[4]
Systemic lupus erythematosus	DISI1SZ7	Strong	Biomarker	[5]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[6]
Bacterial infection	DIS5QJ9S	moderate	Biomarker	[7]
Laryngeal carcinoma	DISNHCIV	moderate	Genetic Variation	[8]
Laryngeal disorder	DISDKUQO	moderate	Biomarker	[8]
Laryngeal squamous cell carcinoma	DIS9UUVF	moderate	Altered Expression	[8]
Neoplasm	DISZKGEW	moderate	Biomarker	[6]
Cutaneous melanoma	DIS3MMH9	Limited	Biomarker	[6]
facioscapulohumeral muscular dystrophy	DISSE0H0	Limited	Altered Expression	[9]

8 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 CCR4-NOT transcription complex subunit 8 (CNOT8).	[10]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of CCR4-NOT transcription complex subunit 8 (CNOT8).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of CCR4-NOT transcription complex subunit 8 (CNOT8).	[12]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of CCR4-NOT transcription complex subunit 8 (CNOT8).	[13]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of CCR4-NOT transcription complex subunit 8 (CNOT8).	[14]
Selenium	DM25CGV	Approved	Selenium decreases the expression of CCR4-NOT transcription complex subunit 8 (CNOT8).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of CCR4-NOT transcription complex subunit 8 (CNOT8).	[16]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of CCR4-NOT transcription complex subunit 8 (CNOT8).	[17]

References

• [1] Antibody against chromatin assembly factor-1 is a novel autoantibody specifically recognized in systemic lupus erythematosus.Lupus. 2014 Sep;23(10):1031-41. doi: 10.1177/0961203314536245. Epub 2014 May 16.
• [2] Clinical significance and prognostic value of chromatin assembly factor-1 overexpression in human solid tumours.Histopathology. 2010 Nov;57(5):716-24. doi: 10.1111/j.1365-2559.2010.03681.x.
• [3] Novel biomarkers for prostate cancer including noncoding transcripts.Am J Pathol. 2009 Dec;175(6):2264-76. doi: 10.2353/ajpath.2009.080868. Epub 2009 Nov 5.
• [4] CAF-1 Subunits Levels Suggest Combined Treatments with PARP-Inhibitors and Ionizing Radiation in Advanced HNSCC.Cancers (Basel). 2019 Oct 17;11(10):1582. doi: 10.3390/cancers11101582.
• [5] Antiribonuclease H2 antibodies are an immune biomarker for systemic lupus erythematosus.Autoimmunity. 2017 Jun;50(4):241-246. doi: 10.1080/08916934.2017.1329422. Epub 2017 May 27.
• [6] Tissue microarray-based evaluation of Chromatin Assembly Factor-1 (CAF-1)/p60 as tumour prognostic marker.Int J Mol Sci. 2012;13(9):11044-11062. doi: 10.3390/ijms130911044. Epub 2012 Sep 5.
• [7] Pyrin-only protein 2 limits inflammation but improves protection against bacteria.Nat Commun. 2017 Jun 5;8:15564. doi: 10.1038/ncomms15564.
• [8] Overexpression of chromatin assembly factor-1/p60 predicts biological behaviour of laryngeal carcinomas.Acta Otorhinolaryngol Ital. 2017 Feb;37(1):17-24. doi: 10.14639/0392-100X-867.
• [9] NuRD and CAF-1-mediated silencing of the D4Z4 array is modulated by DUX4-induced MBD3L proteins.Elife. 2018 Mar 13;7:e31023. doi: 10.7554/eLife.31023.
• [10] 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.
• [11] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [12] 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.
• [13] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [14] 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.
• [15] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [16] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [17] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.