Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQU0EUO)

• DOT Name: DDB1- and CUL4-associated factor 4 (DCAF4)
• Synonyms: WD repeat-containing protein 21A
• Gene Name: DCAF4
• Related Disease:
  Adenocarcinoma
  Lung adenocarcinoma
  Lung cancer
  Lung carcinoma
  Neoplasm
  Squamous cell carcinoma
• UniProt ID: DCAF4_HUMAN
• PDB ID: 3I8C
• Pfam ID: PF00400
• Sequence:
  MNKSRWQSRRRHGRRSHQQNPWFRLRDSEDRSDSRAAQPAHDSGHGDDESPSTSSGTAGT
  SSVPELPGFYFDPEKKRYFRLLPGHNNCNPLTKESIRQKEMESKRLRLLQEEDRRKKIAR
  MGFNASSMLRKSQLGFLNVTNYCHLAHELRLSCMERKKVQIRSMDPSALASDRFNLILAD
  TNSDRLFTVNDVKVGGSKYGIINLQSLKTPTLKVFMHENLYFTNRKVNSVCWASLNHLDS
  HILLCLMGLAETPGCATLLPASLFVNSHPGIDRPGMLCSFRIPGAWSCAWSLNIQANNCF
  STGLSRRVLLTNVVTGHRQSFGTNSDVLAQQFALMAPLLFNGCRSGEIFAIDLRCGNQGK
  GWKATRLFHDSAVTSVRILQDEQYLMASDMAGKIKLWDLRTTKCVRQYEGHVNEYAYLPL
  HVHEEEGILVAVGQDCYTRIWSLHDARLLRTIPSPYPASKADIPSVAFSSRLGGSRGAPG
  LLMAVGQDLYCYSYS
• Function: May function as a substrate receptor for CUL4-DDB1 E3 ubiquitin-protein ligase complex.
• Reactome Pathway: Neddylation (R-HSA-8951664)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adenocarcinoma	DIS3IHTY	Strong	Altered Expression	[1]
Lung adenocarcinoma	DISD51WR	Strong	Altered Expression	[2]
Lung cancer	DISCM4YA	Strong	Genetic Variation	[1]
Lung carcinoma	DISTR26C	Strong	Genetic Variation	[1]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[1]
Squamous cell carcinoma	DISQVIFL	Strong	Altered Expression	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of DDB1- and CUL4-associated factor 4 (DCAF4).	[3]

11 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 DDB1- and CUL4-associated factor 4 (DCAF4).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of DDB1- and CUL4-associated factor 4 (DCAF4).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of DDB1- and CUL4-associated factor 4 (DCAF4).	[6]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of DDB1- and CUL4-associated factor 4 (DCAF4).	[7]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of DDB1- and CUL4-associated factor 4 (DCAF4).	[8]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of DDB1- and CUL4-associated factor 4 (DCAF4).	[9]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of DDB1- and CUL4-associated factor 4 (DCAF4).	[10]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of DDB1- and CUL4-associated factor 4 (DCAF4).	[10]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of DDB1- and CUL4-associated factor 4 (DCAF4).	[11]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of DDB1- and CUL4-associated factor 4 (DCAF4).	[12]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of DDB1- and CUL4-associated factor 4 (DCAF4).	[13]

References

• [1] Functional variants in DCAF4 associated with lung cancer risk in European populations.Carcinogenesis. 2017 May 1;38(5):541-551. doi: 10.1093/carcin/bgx033.
• [2] Integrative analysis of multi-omics data reveals distinct impacts of DDB1-CUL4 associated factors in human lung adenocarcinomas.Sci Rep. 2017 Mar 23;7(1):333. doi: 10.1038/s41598-017-00512-1.
• [3] 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.
• [4] 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.
• [5] 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.
• [6] 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.
• [7] Persistent and non-persistent changes in gene expression result from long-term estrogen exposure of MCF-7 breast cancer cells. J Steroid Biochem Mol Biol. 2011 Feb;123(3-5):140-50.
• [8] 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.
• [9] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [10] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [11] Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.
• [12] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [13] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.