Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1NIIQD)

• DOT Name: CCR4-NOT transcription complex subunit 9 (CNOT9)
• Synonyms: Cell differentiation protein RQCD1 homolog; Rcd-1
• Gene Name: CNOT9
• Related Disease:
  Bladder transitional cell carcinoma
  Breast cancer
  Breast carcinoma
  Cutaneous melanoma
  Gastric adenocarcinoma
  Hepatocellular carcinoma
  Prostate adenocarcinoma
  Triple negative breast cancer
  Melanoma
  Neoplasm
• UniProt ID: CNOT9_HUMAN
• PDB ID: 2FV2; 4CRU; 4CRV; 4CT6; 4CT7; 5LSW; 5ONA; 5ONB; 6HOM; 6HON
• Pfam ID: PF04078
• Sequence:
  MHSLATAAPVPTTLAQVDREKIYQWINELSSPETRENALLELSKKRESVPDLAPMLWHSF
  GTIAALLQEIVNIYPSINPPTLTAHQSNRVCNALALLQCVASHPETRSAFLAAHIPLFLY
  PFLHTVSKTRPFEYLRLTSLGVIGALVKTDEQEVINFLLTTEIIPLCLRIMESGSELSKT
  VATFILQKILLDDTGLAYICQTYERFSHVAMILGKMVLQLSKEPSARLLKHVVRCYLRLS
  DNPRAREALRQCLPDQLKDTTFAQVLKDDTTTKRWLAQLVKNLQEGQVTDPRGIPLPPQ
• Function: Component of the CCR4-NOT complex which is one of the major cellular mRNA deadenylases and is linked to various cellular processes including bulk mRNA degradation, miRNA-mediated repression, translational repression during translational initiation and general transcription regulation. Additional complex functions may be a consequence of its influence on mRNA expression. Involved in down-regulation of MYB- and JUN-dependent transcription. May play a role in cell differentiation. Can bind oligonucleotides, such as poly-G, poly-C or poly-T (in vitro), but the physiological relevance of this is not certain. Does not bind poly-A. Enhances ligand-dependent transcriptional activity of nuclear hormone receptors, including RARA, expect ESR1-mediated transcription that is not only slightly increased, if at all.
• Tissue Specificity: Detected in spleen, thymus, prostate, testis, ovary and intestine.
• KEGG Pathway: R. degradation (hsa03018)
• Reactome Pathway:
  Activation of anterior HOX genes in hindbrain development during early embryogenesis (R-HSA-5617472)
  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

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bladder transitional cell carcinoma	DISNL46A	Strong	Genetic Variation	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[2]
Cutaneous melanoma	DIS3MMH9	Strong	Genetic Variation	[1]
Gastric adenocarcinoma	DISWWLTC	Strong	Genetic Variation	[1]
Hepatocellular carcinoma	DIS0J828	Strong	Genetic Variation	[1]
Prostate adenocarcinoma	DISBZYU8	Strong	Genetic Variation	[1]
Triple negative breast cancer	DISAMG6N	Strong	Altered Expression	[3]
Melanoma	DIS1RRCY	moderate	Genetic Variation	[4]
Neoplasm	DISZKGEW	moderate	Biomarker	[3]

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 CCR4-NOT transcription complex subunit 9 (CNOT9).	[5]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of CCR4-NOT transcription complex subunit 9 (CNOT9).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of CCR4-NOT transcription complex subunit 9 (CNOT9).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of CCR4-NOT transcription complex subunit 9 (CNOT9).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of CCR4-NOT transcription complex subunit 9 (CNOT9).	[9]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of CCR4-NOT transcription complex subunit 9 (CNOT9).	[11]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of CCR4-NOT transcription complex subunit 9 (CNOT9).	[12]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of CCR4-NOT transcription complex subunit 9 (CNOT9).	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of CCR4-NOT transcription complex subunit 9 (CNOT9).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of CCR4-NOT transcription complex subunit 9 (CNOT9).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of CCR4-NOT transcription complex subunit 9 (CNOT9).	[15]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of CCR4-NOT transcription complex subunit 9 (CNOT9).	[14]

References

• [1] Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity.Nat Biotechnol. 2016 Feb;34(2):155-63. doi: 10.1038/nbt.3391. Epub 2015 Nov 30.
• [2] Involvement of RQCD1 overexpression, a novel cancer-testis antigen, in the Akt pathway in breast cancer cells.Int J Oncol. 2009 Oct;35(4):673-81.
• [3] Overexpression of miR-361-5p in triple-negative breast cancer (TNBC) inhibits migration and invasion by targeting RQCD1 and inhibiting the EGFR/PI3K/Akt pathway.Bosn J Basic Med Sci. 2019 Feb 12;19(1):52-59. doi: 10.17305/bjbms.2018.3399.
• [4] Whole exome sequencing identifies a recurrent RQCD1 P131L mutation in cutaneous melanoma.Oncotarget. 2015 Jan 20;6(2):1115-27. doi: 10.18632/oncotarget.2747.
• [5] 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.
• [6] 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.
• [7] 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.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [10] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [11] Integrated assessment by multiple gene expression analysis of quercetin bioactivity on anticancer-related mechanisms in colon cancer cells in vitro. Eur J Nutr. 2005 Mar;44(3):143-56. doi: 10.1007/s00394-004-0503-1. Epub 2004 Apr 30.
• [12] Proteomics-based identification of differentially abundant proteins from human keratinocytes exposed to arsenic trioxide. J Proteomics Bioinform. 2014 Jul;7(7):166-178.
• [13] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [14] Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
• [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] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.