Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8UJLZU)

• DOT Name: DCN1-like protein 1 (DCUN1D1)
• Synonyms: DCNL1; DCUN1 domain-containing protein 1; Defective in cullin neddylation protein 1-like protein 1; Squamous cell carcinoma-related oncogene
• Gene Name: DCUN1D1
• Related Disease:
  Glioma
  Adenocarcinoma
  Autism
  Carcinoma
  Cervical cancer
  Cervical carcinoma
  Colorectal carcinoma
  Esophageal squamous cell carcinoma
  Head-neck squamous cell carcinoma
  Laryngeal squamous cell carcinoma
  Metastatic malignant neoplasm
  Minimally invasive lung adenocarcinoma
  Non-small-cell lung cancer
  Parkinson disease
  Prostate cancer
  Prostate carcinoma
  Retinitis pigmentosa
  Advanced cancer
  Amyotrophic lateral sclerosis
  Frontotemporal dementia
  Neoplasm
  Adrenal adenoma
  Adrenocortical carcinoma
  Aplasia cutis congenita
  Corpus callosum, agenesis of
• UniProt ID: DCNL1_HUMAN
• PDB ID: 3TDU; 3TDZ; 4P5O; 5UFI; 5V83; 5V86; 5V88; 6B5Q; 6BG3; 6BG5; 6P5V; 6P5W; 6XOL; 6XOM; 6XON; 6XOO; 6XOP; 6XOQ; 7KWA; 8OR2; 8OR3
• Pfam ID: PF03556 ; PF14555
• Sequence:
  MNKLKSSQKDKVRQFMIFTQSSEKTAVSCLSQNDWKLDVATDNFFQNPELYIRESVKGSL
  DRKKLEQLYNRYKDPQDENKIGIDGIQQFCDDLALDPASISVLIIAWKFRAATQCEFSKQ
  EFMDGMTELGCDSIEKLKAQIPKMEQELKEPGRFKDFYQFTFNFAKNPGQKGLDLEMAIA
  YWNLVLNGRFKFLDLWNKFLLEHHKRSIPKDTWNLLLDFSTMIADDMSNYDEEGAWPVLI
  DDFVEFARPQIAGTKSTTV
• Function: Part of an E3 ubiquitin ligase complex for neddylation. Promotes neddylation of cullin components of E3 cullin-RING ubiquitin ligase complexes. Acts by binding to cullin-RBX1 complexes in the cytoplasm and promoting their nuclear translocation, enhancing recruitment of E2-NEDD8 (UBE2M-NEDD8) thioester to the complex, and optimizing the orientation of proteins in the complex to allow efficient transfer of NEDD8 from the E2 to the cullin substrates. Involved in the release of inhibitory effets of CAND1 on cullin-RING ligase E3 complex assembly and activity. Acts also as an oncogene facilitating malignant transformation and carcinogenic progression.
• Tissue Specificity: Expressed in pancreas, kidney, placenta, brain and heart. Weakly or not expressed in liver, skeletal muscle and lung. Strongly overexpressed in thyroid tumors, bronchioloalveolar carcinomas, and malignant tissues of squamous cell carcinoma of the oral tongue. Not overexpressed in aggressive adrenocortical carcinomas.
• Reactome Pathway: Neddylation (R-HSA-8951664)
• BioCyc Pathway: MetaCyc:ENSG00000043093-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

25 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Glioma	DIS5RPEH	Definitive	Biomarker	[1]
Adenocarcinoma	DIS3IHTY	Strong	Biomarker	[2]
Autism	DISV4V1Z	Strong	Genetic Variation	[3]
Carcinoma	DISH9F1N	Strong	Biomarker	[4]
Cervical cancer	DISFSHPF	Strong	Altered Expression	[5]
Cervical carcinoma	DIST4S00	Strong	Altered Expression	[5]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[6]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[7]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Biomarker	[8]
Laryngeal squamous cell carcinoma	DIS9UUVF	Strong	Biomarker	[9]
Metastatic malignant neoplasm	DIS86UK6	Strong	Altered Expression	[10]
Minimally invasive lung adenocarcinoma	DIS4W83X	Strong	Altered Expression	[2]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[10]
Parkinson disease	DISQVHKL	Strong	Genetic Variation	[11]
Prostate cancer	DISF190Y	Strong	Altered Expression	[12]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[12]
Retinitis pigmentosa	DISCGPY8	Strong	Genetic Variation	[13]
Advanced cancer	DISAT1Z9	moderate	Altered Expression	[10]
Amyotrophic lateral sclerosis	DISF7HVM	moderate	Biomarker	[14]
Frontotemporal dementia	DISKYHXL	moderate	Biomarker	[14]
Neoplasm	DISZKGEW	moderate	Altered Expression	[1]
Adrenal adenoma	DISC2UN8	Limited	Altered Expression	[15]
Adrenocortical carcinoma	DISZF4HX	Limited	Altered Expression	[15]
Aplasia cutis congenita	DISMDAYM	Limited	Altered Expression	[15]
Corpus callosum, agenesis of	DISO9P40	Limited	Altered Expression	[15]

7 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 DCN1-like protein 1 (DCUN1D1).	[16]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of DCN1-like protein 1 (DCUN1D1).	[17]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of DCN1-like protein 1 (DCUN1D1).	[18]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of DCN1-like protein 1 (DCUN1D1).	[19]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of DCN1-like protein 1 (DCUN1D1).	[20]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of DCN1-like protein 1 (DCUN1D1).	[21]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone decreases the expression of DCN1-like protein 1 (DCUN1D1).	[22]

References

• [1] SCCRO promotes glioma formation and malignant progression in mice.Neoplasia. 2010 Jun;12(6):476-84. doi: 10.1593/neo.10202.
• [2] SCCRO expression correlates with invasive progression in bronchioloalveolar carcinoma.Ann Thorac Surg. 2004 Nov;78(5):1734-41. doi: 10.1016/j.athoracsur.2004.05.056.
• [3] Cloning and expression analysis of a novel gene, RP42, mapping to an autism susceptibility locus on 6q16.Genomics. 2000 Apr 1;65(1):70-4. doi: 10.1006/geno.2000.6126.
• [4] SCCRO (DCUN1D1) induces extracellular matrix invasion by activating matrix metalloproteinase 2.Clin Cancer Res. 2008 Nov 1;14(21):6780-9. doi: 10.1158/1078-0432.CCR-08-0719.
• [5] MicroRNA?95 inhibits cell proliferation, migration and invasion by targeting defective in cullin neddylation1 domain containing 1 in cervical cancer.Int J Mol Med. 2018 Aug;42(2):779-788. doi: 10.3892/ijmm.2018.3660. Epub 2018 May 8.
• [6] MicroRNA-520b Functions as a Tumor Suppressor in Colorectal Cancer by Inhibiting Defective in Cullin Neddylation 1 Domain Containing 1 (DCUN1D1).Oncol Res. 2018 May 7;26(4):593-604. doi: 10.3727/096504017X14920318811712. Epub 2017 May 4.
• [7] SnoN overexpression is predictive of poor survival in patients with esophageal squamous cell carcinoma.Ann Surg Oncol. 2008 Oct;15(10):2965-75. doi: 10.1245/s10434-008-9986-y. Epub 2008 Jul 9.
• [8] Distinct effects of alcohol consumption and smoking on genetic alterations in head and neck carcinoma.PLoS One. 2013 Nov 20;8(11):e80828. doi: 10.1371/journal.pone.0080828. eCollection 2013.
• [9] Expression of DCUN1D1 in laryngeal squamous cell carcinoma and its inhibiting effect on TU-177 cells after interfered by RNA.Clin Exp Pharmacol Physiol. 2018 May;45(5):461-466. doi: 10.1111/1440-1681.12893. Epub 2017 Dec 21.
• [10] DCUN1D1 facilitates tumor metastasis by activating FAK signaling and up-regulates PD-L1 in non-small-cell lung cancer.Exp Cell Res. 2019 Jan 15;374(2):304-314. doi: 10.1016/j.yexcr.2018.12.001. Epub 2018 Dec 4.
• [11] Web-based genome-wide association study identifies two novel loci and a substantial genetic component for Parkinson's disease.PLoS Genet. 2011 Jun;7(6):e1002141. doi: 10.1371/journal.pgen.1002141. Epub 2011 Jun 23.
• [12] Clinical significance of SCCRO (DCUN1D1) in prostate cancer and its proliferation-inhibiting effect on Lncap cells.Eur Rev Med Pharmacol Sci. 2017 Oct;21(19):4283-4291.
• [13] Mutations in a BTB-Kelch protein, KLHL7, cause autosomal-dominant retinitis pigmentosa. Am J Hum Genet. 2009 Jun;84(6):792-800. doi: 10.1016/j.ajhg.2009.05.007.
• [14] Recent advances in the genetics of amyotrophic lateral sclerosis and frontotemporal dementia: common pathways in neurodegenerative disease.Hum Mol Genet. 2006 Oct 15;15 Spec No 2:R182-7. doi: 10.1093/hmg/ddl202.
• [15] Squamous cell carcinoma-related oncogene is highly expressed in developing, normal, and adenomatous adrenal tissue but not in aggressive adrenocortical carcinomas.Surgery. 2004 Dec;136(6):1122-8. doi: 10.1016/j.surg.2004.06.041.
• [16] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [17] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [18] 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.
• [19] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [20] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [21] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [22] Evaluation of an in vitro model of androgen ablation and identification of the androgen responsive proteome in LNCaP cells. Proteomics. 2007 Jan;7(1):47-63.