Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3EYK1J)

• DOT Name: DDB1- and CUL4-associated factor 6 (DCAF6)
• Synonyms: Androgen receptor complex-associated protein; ARCAP; IQ motif and WD repeat-containing protein 1; Nuclear receptor interaction protein; NRIP
• Gene Name: DCAF6
• Related Disease:
  Cardiac failure
  Cardiomyopathy
  Congestive heart failure
  Limb-girdle muscular dystrophy
  Metastatic prostate carcinoma
  Neoplasm
  Osteoporosis
  Prostate cancer
  Prostate carcinoma
  Prostate neoplasm
  Breast cancer
  Breast carcinoma
  Gastric cancer
  Stomach cancer
  Acute myelogenous leukaemia
  Cervical cancer
• UniProt ID: DCAF6_HUMAN
• PDB ID: 3I7O
• Pfam ID: PF00400
• Sequence:
  MSRGGSYPHLLWDVRKRSLGLEDPSRLRSRYLGRREFIQRLKLEATLNVHDGCVNTICWN
  DTGEYILSGSDDTKLVISNPYSRKVLTTIRSGHRANIFSAKFLPCTNDKQIVSCSGDGVI
  FYTNVEQDAETNRQCQFTCHYGTTYEIMTVPNDPYTFLSCGEDGTVRWFDTRIKTSCTKE
  DCKDDILINCRRAATSVAICPPIPYYLAVGCSDSSVRIYDRRMLGTRATGNYAGRGTTGM
  VARFIPSHLNNKSCRVTSLCYSEDGQEILVSYSSDYIYLFDPKDDTARELKTPSAEERRE
  ELRQPPVKRLRLRGDWSDTGPRARPESERERDGEQSPNVSLMQRMSDMLSRWFEEASEVA
  QSNRGRGRSRPRGGTSQSDISTLPTVPSSPDLEVSETAMEVDTPAEQFLQPSTSSTMSAQ
  AHSTSSPTESPHSTPLLSSPDSEQRQSVEASGHHTHHQSDNNNEKLSPKPGTGEPVLSLH
  YSTEGTTTSTIKLNFTDEWSSIASSSRGIGSHCKSEGQEESFVPQSSVQPPEGDSETKAP
  EESSEDVTKYQEGVSAENPVENHINITQSDKFTAKPLDSNSGERNDLNLDRSCGVPEESA
  SSEKAKEPETSDQTSTESATNENNTNPEPQFQTEATGPSAHEETSTRDSALQDTDDSDDD
  PVLIPGARYRAGPGDRRSAVARIQEFFRRRKERKEMEELDTLNIRRPLVKMVYKGHRNSR
  TMIKEANFWGANFVMSGSDCGHIFIWDRHTAEHLMLLEADNHVVNCLQPHPFDPILASSG
  IDYDIKIWSPLEESRIFNRKLADEVITRNELMLEETRNTITVPASFMLRMLASLNHIRAD
  RLEGDRSEGSGQENENEDEE
• Function: Ligand-dependent coactivator of nuclear receptors. Enhance transcriptional activity of the nuclear receptors NR3C1 and AR. May function as a substrate receptor for CUL4-DDB1 E3 ubiquitin-protein ligase complex.
• Tissue Specificity: Highly expressed in skeletal muscle and testis. Expressed to a lesser degree in heart, prostate, and adrenal gland.
• Reactome Pathway: Neddylation (R-HSA-8951664)

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cardiac failure	DISDC067	Strong	Biomarker	[1]
Cardiomyopathy	DISUPZRG	Strong	Biomarker	[1]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[1]
Limb-girdle muscular dystrophy	DISI9Y1Z	Strong	Biomarker	[1]
Metastatic prostate carcinoma	DISVBEZ9	Strong	Altered Expression	[2]
Neoplasm	DISZKGEW	Strong	Biomarker	[3]
Osteoporosis	DISF2JE0	Strong	Biomarker	[4]
Prostate cancer	DISF190Y	Strong	Biomarker	[3]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[3]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[5]
Breast cancer	DIS7DPX1	moderate	Altered Expression	[6]
Breast carcinoma	DIS2UE88	moderate	Altered Expression	[6]
Gastric cancer	DISXGOUK	Disputed	Biomarker	[7]
Stomach cancer	DISKIJSX	Disputed	Biomarker	[7]
Acute myelogenous leukaemia	DISCSPTN	Limited	Genetic Variation	[8]
Cervical cancer	DISFSHPF	Limited	Altered Expression	[9]

5 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 DDB1- and CUL4-associated factor 6 (DCAF6).	[10]
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of DDB1- and CUL4-associated factor 6 (DCAF6).	[14]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of DDB1- and CUL4-associated factor 6 (DCAF6).	[20]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of DDB1- and CUL4-associated factor 6 (DCAF6).	[22]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of DDB1- and CUL4-associated factor 6 (DCAF6).	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of DDB1- and CUL4-associated factor 6 (DCAF6).	[11]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of DDB1- and CUL4-associated factor 6 (DCAF6).	[12]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of DDB1- and CUL4-associated factor 6 (DCAF6).	[13]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of DDB1- and CUL4-associated factor 6 (DCAF6).	[15]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of DDB1- and CUL4-associated factor 6 (DCAF6).	[16]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of DDB1- and CUL4-associated factor 6 (DCAF6).	[17]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of DDB1- and CUL4-associated factor 6 (DCAF6).	[18]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of DDB1- and CUL4-associated factor 6 (DCAF6).	[19]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of DDB1- and CUL4-associated factor 6 (DCAF6).	[21]

References

• [1] Deficiency of nuclear receptor interaction protein leads to cardiomyopathy by disrupting sarcomere structure and mitochondrial respiration.J Mol Cell Cardiol. 2019 Dec;137:9-24. doi: 10.1016/j.yjmcc.2019.09.009. Epub 2019 Oct 17.
• [2] Amplification and overexpression of prosaposin in prostate cancer.Genes Chromosomes Cancer. 2005 Dec;44(4):351-64. doi: 10.1002/gcc.20249.
• [3] NRIP/DCAF6 stabilizes the androgen receptor protein by displacing DDB2 from the CUL4A-DDB1 E3 ligase complex in prostate cancer.Oncotarget. 2017 Mar 28;8(13):21501-21515. doi: 10.18632/oncotarget.15308.
• [4] Estrogen-related genes and postmenopausal osteoporosis risk.Climacteric. 2012 Dec;15(6):587-93. doi: 10.3109/13697137.2012.656160. Epub 2012 Feb 15.
• [5] The bromodomain protein BRD4 regulates the KEAP1/NRF2-dependent oxidative stress response.Cell Death Dis. 2014 Apr 24;5(4):e1195. doi: 10.1038/cddis.2014.157.
• [6] Identification of androgen-responsive microRNAs and androgen-related genes in breast cancer.Anticancer Res. 2013 Nov;33(11):4811-9.
• [7] Enhanced expression of circular RNA circ-DCAF6 predicts adverse prognosis and promotes cell progression via sponging miR-1231 and miR-1256 in gastric cancer.Exp Mol Pathol. 2019 Oct;110:104273. doi: 10.1016/j.yexmp.2019.104273. Epub 2019 Jun 19.
• [8] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [9] NRIP, a novel nuclear receptor interaction protein, enhances the transcriptional activity of nuclear receptors.J Biol Chem. 2005 May 20;280(20):20000-9. doi: 10.1074/jbc.M412169200. Epub 2005 Mar 21.
• [10] 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.
• [11] 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.
• [12] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [13] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [14] Identification of novel gene targets and putative regulators of arsenic-associated DNA methylation in human urothelial cells and bladder cancer. Chem Res Toxicol. 2015 Jun 15;28(6):1144-55. doi: 10.1021/tx500393y. Epub 2015 Jun 3.
• [15] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [16] 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.
• [17] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [18] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [19] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [20] 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.
• [21] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [22] 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.