Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTG9AAG0)

• DOT Name: COP9 signalosome complex subunit 6 (COPS6)
• Synonyms: SGN6; Signalosome subunit 6; JAB1-containing signalosome subunit 6; MOV34 homolog; Vpr-interacting protein; hVIP
• Gene Name: COPS6
• Related Disease:
  Colorectal carcinoma
  Gastric cancer
  Stomach cancer
  Thyroid gland papillary carcinoma
  Breast cancer
  Breast carcinoma
  Carcinoma
  Cervical cancer
  Cervical carcinoma
  Colon cancer
  Colon carcinoma
  Hepatocellular carcinoma
  HIV infectious disease
  Thyroid tumor
  Neoplasm
  Adult glioblastoma
  Advanced cancer
  Glioblastoma multiforme
  Lung adenocarcinoma
  Matthew-Wood syndrome
  Myeloproliferative neoplasm
  Pancreatic cancer
  Pancreatic ductal carcinoma
• UniProt ID: CSN6_HUMAN
• PDB ID: 4D10; 4D18; 4QFT; 4R14; 4WSN; 6R6H; 6R7F; 6R7H; 6R7I; 8H38; 8H3A; 8H3F
• Pfam ID: PF01398 ; PF13012
• Sequence:
  MAAAAAAAAATNGTGGSSGMEVDAAVVPSVMACGVTGSVSVALHPLVILNISDHWIRMRS
  QEGRPVQVIGALIGKQEGRNIEVMNSFELLSHTVEEKIIIDKEYYYTKEEQFKQVFKELE
  FLGWYTTGGPPDPSDIHVHKQVCEIIESPLFLKLNPMTKHTDLPVSVFESVIDIINGEAT
  MLFAELTYTLATEEAERIGVDHVARMTATGSGENSTVAEHLIAQHSAIKMLHSRVKLILE
  YVKASEAGEVPFNHEILREAYALCHCLPVLSTDKFKTDFYDQCNDVGLMAYLGTITKTCN
  TMNQFVNKFNVLYDRQGIGRRMRGLFF
• Function: Component of the COP9 signalosome complex (CSN), a complex involved in various cellular and developmental processes. The CSN complex is an essential regulator of the ubiquitin (Ubl) conjugation pathway by mediating the deneddylation of the cullin subunits of SCF-type E3 ligase complexes, leading to decrease the Ubl ligase activity of SCF-type complexes such as SCF, CSA or DDB2. The complex is also involved in phosphorylation of p53/TP53, c-jun/JUN, IkappaBalpha/NFKBIA, ITPK1 and IRF8, possibly via its association with CK2 and PKD kinases. CSN-dependent phosphorylation of TP53 and JUN promotes and protects degradation by the Ubl system, respectively. Has some glucocorticoid receptor-responsive activity. Stabilizes COP1 through reducing COP1 auto-ubiquitination and decelerating COP1 turnover rate, hence regulates the ubiquitination of COP1 targets.
• Tissue Specificity: Widely expressed.
• Reactome Pathway:
  Formation of TC-NER Pre-Incision Complex (R-HSA-6781823)
  Cargo recognition for clathrin-mediated endocytosis (R-HSA-8856825)
  Neddylation (R-HSA-8951664)
  DNA Damage Recognition in GG-NER (R-HSA-5696394)

Molecular Interaction Atlas (MIA) of This DOT

23 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Colorectal carcinoma	DIS5PYL0	Definitive	Altered Expression	[1]
Gastric cancer	DISXGOUK	Definitive	Biomarker	[2]
Stomach cancer	DISKIJSX	Definitive	Biomarker	[2]
Thyroid gland papillary carcinoma	DIS48YMM	Definitive	Altered Expression	[3]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[1]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[1]
Carcinoma	DISH9F1N	Strong	Altered Expression	[1]
Cervical cancer	DISFSHPF	Strong	Altered Expression	[4]
Cervical carcinoma	DIST4S00	Strong	Altered Expression	[4]
Colon cancer	DISVC52G	Strong	Biomarker	[5]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[5]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[6]
HIV infectious disease	DISO97HC	Strong	Biomarker	[7]
Thyroid tumor	DISLVKMD	Strong	Altered Expression	[8]
Neoplasm	DISZKGEW	moderate	Biomarker	[2]
Adult glioblastoma	DISVP4LU	Limited	Biomarker	[9]
Advanced cancer	DISAT1Z9	Limited	Altered Expression	[10]
Glioblastoma multiforme	DISK8246	Limited	Biomarker	[9]
Lung adenocarcinoma	DISD51WR	Limited	Biomarker	[11]
Matthew-Wood syndrome	DISA7HR7	Limited	Altered Expression	[12]
Myeloproliferative neoplasm	DIS5KAPA	Limited	Biomarker	[11]
Pancreatic cancer	DISJC981	Limited	Altered Expression	[12]
Pancreatic ductal carcinoma	DIS26F9Q	Limited	Biomarker	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of COP9 signalosome complex subunit 6 (COPS6).	[13]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of COP9 signalosome complex subunit 6 (COPS6).	[14]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of COP9 signalosome complex subunit 6 (COPS6).	[15]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of COP9 signalosome complex subunit 6 (COPS6).	[16]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of COP9 signalosome complex subunit 6 (COPS6).	[17]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of COP9 signalosome complex subunit 6 (COPS6).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of COP9 signalosome complex subunit 6 (COPS6).	[19]

References

• [1] The prognostic value of CSN6 expression in upper tract urothelial carcinomas.Kaohsiung J Med Sci. 2019 Sep;35(9):559-565. doi: 10.1002/kjm2.12104. Epub 2019 Jul 24.
• [2] CSN6 promotes tumorigenesis of gastric cancer by ubiquitin-independent proteasomal degradation of p16(INK4a).Cancer Biol Med. 2019 Aug;16(3):514-529. doi: 10.20892/j.issn.2095-3941.2018.0410.
• [3] Downregulation of CSN6 attenuates papillary thyroid carcinoma progression by reducing Wnt/-catenin signaling and sensitizes cancer cells to FH535 therapy.Cancer Med. 2018 Feb;7(2):285-296. doi: 10.1002/cam4.1272. Epub 2018 Jan 17.
• [4] CSN6 Promotes the Migration and Invasion of Cervical Cancer Cells by Inhibiting Autophagic Degradation of Cathepsin L.Int J Biol Sci. 2019 May 12;15(6):1310-1324. doi: 10.7150/ijbs.32987. eCollection 2019.
• [5] ERK2-Dependent Phosphorylation of CSN6 Is Critical in Colorectal Cancer Development.Cancer Cell. 2015 Aug 10;28(2):183-97. doi: 10.1016/j.ccell.2015.07.004.
• [6] Overexpression of CSN6 promotes the epithelial-mesenchymal transition and predicts poor prognosis in hepatocellular carcinoma.Clin Res Hepatol Gastroenterol. 2020 Jun;44(3):340-348. doi: 10.1016/j.clinre.2019.07.012. Epub 2019 Aug 14.
• [7] Host cell gene expression during human immunodeficiency virus type 1 latency and reactivation and effects of targeting genes that are differentially expressed in viral latency.J Virol. 2004 Sep;78(17):9458-73. doi: 10.1128/JVI.78.17.9458-9473.2004.
• [8] Subunit 6 of the COP9 signalosome promotes tumorigenesis in mice through stabilization of MDM2 and is upregulated in human cancers.J Clin Invest. 2011 Mar;121(3):851-65. doi: 10.1172/JCI44111. Epub 2011 Feb 7.
• [9] CSN6 controls the proliferation and metastasis of glioblastoma by CHIP-mediated degradation of EGFR.Oncogene. 2017 Feb 23;36(8):1134-1144. doi: 10.1038/onc.2016.280. Epub 2016 Aug 22.
• [10] The Emerging Role of CSN6 in Biological Behavior and Cancer Progress.Anticancer Agents Med Chem. 2019;19(10):1198-1204. doi: 10.2174/1871520619666190408142131.
• [11] COP9 signalosome subunit CSN5, but not CSN6, is upregulated in lung adenocarcinoma and predicts poor prognosis.J Thorac Dis. 2018 Mar;10(3):1596-1606. doi: 10.21037/jtd.2018.02.09.
• [12] CSN6 expression is associated with pancreatic cancer progression and predicts poor prognosis.Cancer Biol Ther. 2019;20(9):1290-1299. doi: 10.1080/15384047.2019.1632143. Epub 2019 Jul 16.
• [13] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [14] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [15] 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.
• [16] Proteomics-based identification of differentially abundant proteins from human keratinocytes exposed to arsenic trioxide. J Proteomics Bioinform. 2014 Jul;7(7):166-178.
• [17] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [18] 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.
• [19] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.