Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZWPJ24)

• DOT Name: COP9 signalosome complex subunit 3 (COPS3)
• Synonyms: SGN3; Signalosome subunit 3; JAB1-containing signalosome subunit 3
• Gene Name: COPS3
• Related Disease:
  Advanced cancer
  Bone osteosarcoma
  Clear cell renal carcinoma
  Hepatocellular carcinoma
  Kidney cancer
  Lung cancer
  Lung carcinoma
  Prostate cancer
  Prostate carcinoma
  Renal carcinoma
  Smith-Magenis syndrome
  Neoplasm
  Metastatic malignant neoplasm
• UniProt ID: CSN3_HUMAN
• PDB ID: 4D10; 4D18; 4WSN; 6R6H; 6R7F; 6R7H; 6R7I; 6R7N; 8H38; 8H3A; 8H3F
• Pfam ID: PF21215 ; PF01399
• Sequence:
  MASALEQFVNSVRQLSAQGQMTQLCELINKSGELLAKNLSHLDTVLGALDVQEHSLGVLA
  VLFVKFSMPSVPDFETLFSQVQLFISTCNGEHIRYATDTFAGLCHQLTNALVERKQPLRG
  IGILKQAIDKMQMNTNQLTSIHADLCQLCLLAKCFKPALPYLDVDMMDICKENGAYDAKH
  FLCYYYYGGMIYTGLKNFERALYFYEQAITTPAMAVSHIMLESYKKYILVSLILLGKVQQ
  LPKYTSQIVGRFIKPLSNAYHELAQVYSTNNPSELRNLVNKHSETFTRDNNMGLVKQCLS
  SLYKKNIQRLTKTFLTLSLQDMASRVQLSGPQEAEKYVLHMIEDGEIFASINQKDGMVSF
  HDNPEKYNNPAMLHNIDQEMLKCIELDERLKAMDQEITVNPQFVQKSMGSQEDDSGNKPS
  SYS
• 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/ICSBP, 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.
• Tissue Specificity: Widely expressed. Expressed at high level in heart and skeletal muscle.
• 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

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Bone osteosarcoma	DIST1004	Strong	Biomarker	[2]
Clear cell renal carcinoma	DISBXRFJ	Strong	Altered Expression	[1]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[2]
Kidney cancer	DISBIPKM	Strong	Biomarker	[1]
Lung cancer	DISCM4YA	Strong	Altered Expression	[3]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[3]
Prostate cancer	DISF190Y	Strong	Biomarker	[2]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[2]
Renal carcinoma	DISER9XT	Strong	Biomarker	[1]
Smith-Magenis syndrome	DISG4G6X	Strong	Biomarker	[4]
Neoplasm	DISZKGEW	Disputed	Biomarker	[5]
Metastatic malignant neoplasm	DIS86UK6	Limited	Altered Expression	[6]

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 COP9 signalosome complex subunit 3 (COPS3).	[7]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of COP9 signalosome complex subunit 3 (COPS3).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of COP9 signalosome complex subunit 3 (COPS3).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of COP9 signalosome complex subunit 3 (COPS3).	[10]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of COP9 signalosome complex subunit 3 (COPS3).	[11]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of COP9 signalosome complex subunit 3 (COPS3).	[12]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of COP9 signalosome complex subunit 3 (COPS3).	[13]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of COP9 signalosome complex subunit 3 (COPS3).	[14]

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 decreases the methylation of COP9 signalosome complex subunit 3 (COPS3).	[15]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of COP9 signalosome complex subunit 3 (COPS3).	[16]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of COP9 signalosome complex subunit 3 (COPS3).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of COP9 signalosome complex subunit 3 (COPS3).	[18]

References

• [1] Overexpression of COPS3 promotes clear cell renal cell carcinoma progression via regulation of Phospho-AKT(Thr308), Cyclin D1 and Caspase-3.Exp Cell Res. 2018 Apr 15;365(2):163-170. doi: 10.1016/j.yexcr.2018.02.025. Epub 2018 Feb 23.
• [2] Knockdown of COPS3 inhibits the progress of prostate cancer through reducing phosphorylated p38 MAPK expression and impairs the epithelial-mesenchymal transition process.Prostate. 2019 Dec;79(16):1823-1831. doi: 10.1002/pros.23907. Epub 2019 Sep 11.
• [3] Silencing of the COPS3 gene by siRNA reduces proliferation of lung cancer cells most likely via induction of cell cycle arrest and apoptosis.Asian Pac J Cancer Prev. 2012;13(3):1043-8. doi: 10.7314/apjcp.2012.13.3.1043.
• [4] Hemizygosity for the COP9 signalosome subunit gene, SGN3, in the Smith-Magenis syndrome.Am J Med Genet. 1999 Dec 3;87(4):342-8.
• [5] COPS3 amplification and clinical outcome in osteosarcoma.Cancer. 2007 May 1;109(9):1870-6. doi: 10.1002/cncr.22595.
• [6] Novel oncogene COPS3 interacts with Beclin1 and Raf-1 to regulate metastasis of osteosarcoma through autophagy.J Exp Clin Cancer Res. 2018 Jul 3;37(1):135. doi: 10.1186/s13046-018-0791-6.
• [7] 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.
• [8] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [9] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [10] Expression Profiling of Human Pluripotent Stem Cell-Derived Cardiomyocytes Exposed to Doxorubicin-Integration and Visualization of Multi-Omics Data. Toxicol Sci. 2018 May 1;163(1):182-195. doi: 10.1093/toxsci/kfy012.
• [11] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [12] 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.
• [13] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [14] Interactive gene expression pattern in prostate cancer cells exposed to phenolic antioxidants. Life Sci. 2002 Mar 1;70(15):1821-39.
• [15] 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.
• [16] 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.
• [17] 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.
• [18] 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.