Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTG20VWE)

• DOT Name: DCN1-like protein 3 (DCUN1D3)
• Synonyms: DCNL3; DCUN1 domain-containing protein 3; Defective in cullin neddylation protein 1-like protein 3; Squamous cell carcinoma-related oncogene 3
• Gene Name: DCUN1D3
• Related Disease: Neoplasm
• UniProt ID: DCNL3_HUMAN
• PDB ID: 4GBA
• Pfam ID: PF03556
• Sequence:
  MGQCVTKCKNPSSTLGSKNGDREPSNKSHSRRGAGHREEQVPPCGKPGGDILVNGTKKAE
  AATEACQLPTSSGDAGRESKSNAEESSLQRLEELFRRYKDEREDAILEEGMERFCNDLCV
  DPTEFRVLLLAWKFQAATMCKFTRKEFFDGCKAISADSIDGICARFPSLLTEAKQEDKFK
  DLYRFTFQFGLDSEEGQRSLHREIAIALWKLVFTQNNPPVLDQWLNFLTENPSGIKGISR
  DTWNMFLNFTQVIGPDLSNYSEDEAWPSLFDTFVEWEMERRKREGEGRGALSSGPEGLCP
  EEQT
• Function: Contributes to the neddylation of all cullins by transferring NEDD8 from N-terminally acetylated NEDD8-conjugating E2s enzyme to different cullin C-terminal domain-RBX complexes and may play a role in the cell cycle progression by regulating the SCF ubiquitin E3 ligase complex, after UV damage. At the cell membrane, can promote and as well inhibit cullins neddylation.
• Tissue Specificity: Tends to be down-regulated in different type of cancers, including lung neuroendocrine carcinoma, thyroid Huerthle cell carcinoma and lung squamous cell carcinoma . Mostly expressed in testis and brain . Highly expressed in liver, bladder and renal normal tissue than their tumor tissue counterparts . Palmitoylation stabilizes DCUN1D3 at the cell membrane .
• Reactome Pathway: Neddylation (R-HSA-8951664)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neoplasm	DISZKGEW	Definitive	Biomarker	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of DCN1-like protein 3 (DCUN1D3).	[2]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of DCN1-like protein 3 (DCUN1D3).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of DCN1-like protein 3 (DCUN1D3).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of DCN1-like protein 3 (DCUN1D3).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of DCN1-like protein 3 (DCUN1D3).	[5]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of DCN1-like protein 3 (DCUN1D3).	[6]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of DCN1-like protein 3 (DCUN1D3).	[7]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the expression of DCN1-like protein 3 (DCUN1D3).	[8]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of DCN1-like protein 3 (DCUN1D3).	[9]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of DCN1-like protein 3 (DCUN1D3).	[11]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of DCN1-like protein 3 (DCUN1D3).	[12]

References

• [1] SCCRO3 (DCUN1D3) antagonizes the neddylation and oncogenic activity of SCCRO (DCUN1D1).J Biol Chem. 2014 Dec 12;289(50):34728-42. doi: 10.1074/jbc.M114.585505. Epub 2014 Oct 27.
• [2] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [3] 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.
• [4] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [7] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [8] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [9] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [10] 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.
• [11] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [12] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.