Details of Drug Off-Target (DOT)

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

• DOT Name: Probable ATP-dependent RNA helicase DDX6 (DDX6)
• Synonyms: EC 3.6.4.13; ATP-dependent RNA helicase p54; DEAD box protein 6; Oncogene RCK
• Gene Name: DDX6
• Related Disease:
  B-cell neoplasm
  Dengue
  Gastric cancer
  Glioma
  Haematological malignancy
  Hepatitis C virus infection
  Hepatocellular carcinoma
  Intellectual developmental disorder with impaired language and dysmorphic facies
  Intellectual disability
  Intellectual disability, autosomal dominant 40
  Metastatic malignant neoplasm
  Neoplasm
  Neurodevelopmental disorder
  Primary biliary cholangitis
  Rheumatoid arthritis
  Stomach cancer
  Systemic lupus erythematosus
  Systemic sclerosis
  Vitiligo
  Zika virus infection
  Adult glioblastoma
  Autoimmune disease
  Glioblastoma multiforme
  Immune system disorder
  Syndromic intellectual disability
  Kaposi sarcoma
  Adult lymphoma
  Advanced cancer
  Colorectal carcinoma
  Lymphoma
  MALT lymphoma
  Myotonic dystrophy
  Myotonic dystrophy type 1
  Nodal marginal zone lymphoma
  Pediatric lymphoma
• UniProt ID: DDX6_HUMAN
• PDB ID: 1VEC; 2WAX; 2WAY; 4CRW; 4CT4; 4CT5; 5ANR; 6F9S; 6S8S
• EC Number: 3.6.4.13
• Pfam ID: PF00270 ; PF00271
• Sequence:
  MSTARTENPVIMGLSSQNGQLRGPVKPTGGPGGGGTQTQQQMNQLKNTNTINNGTQQQAQ
  SMTTTIKPGDDWKKTLKLPPKDLRIKTSDVTSTKGNEFEDYCLKRELLMGIFEMGWEKPS
  PIQEESIPIALSGRDILARAKNGTGKSGAYLIPLLERLDLKKDNIQAMVIVPTRELALQV
  SQICIQVSKHMGGAKVMATTGGTNLRDDIMRLDDTVHVVIATPGRILDLIKKGVAKVDHV
  QMIVLDEADKLLSQDFVQIMEDIILTLPKNRQILLYSATFPLSVQKFMNSHLQKPYEINL
  MEELTLKGVTQYYAYVTERQKVHCLNTLFSRLQINQSIIFCNSSQRVELLAKKISQLGYS
  CFYIHAKMRQEHRNRVFHDFRNGLCRNLVCTDLFTRGIDIQAVNVVINFDFPKLAETYLH
  RIGRSGRFGHLGLAINLITYDDRFNLKSIEEQLGTEIKPIPSNIDKSLYVAEYHSEPVED
  EKP
• Function: Essential for the formation of P-bodies, cytosolic membrane-less ribonucleoprotein granules involved in RNA metabolism through the coordinated storage of mRNAs encoding regulatory functions. Plays a role in P-bodies to coordinate the storage of translationally inactive mRNAs in the cytoplasm and prevent their degradation. In the process of mRNA degradation, plays a role in mRNA decapping. Blocks autophagy in nutrient-rich conditions by repressing the expression of ATG-related genes through degradation of their transcripts.
• Tissue Specificity: Abundantly expressed in most tissues.
• KEGG Pathway: R. degradation (hsa03018)
• Reactome Pathway: mRNA decay by 5' to 3' exoribonuclease (R-HSA-430039)

Molecular Interaction Atlas (MIA) of This DOT

35 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
B-cell neoplasm	DISVY326	Strong	Biomarker	[1]
Dengue	DISKH221	Strong	Biomarker	[2]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[1]
Glioma	DIS5RPEH	Strong	Biomarker	[3]
Haematological malignancy	DISCDP7W	Strong	Genetic Variation	[4]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[5]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[1]
Intellectual developmental disorder with impaired language and dysmorphic facies	DISL5LNC	Strong	Autosomal dominant	[6]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[6]
Intellectual disability, autosomal dominant 40	DISAI0IH	Strong	Autosomal dominant	[6]
Metastatic malignant neoplasm	DIS86UK6	Strong	Biomarker	[7]
Neoplasm	DISZKGEW	Strong	Biomarker	[8]
Neurodevelopmental disorder	DIS372XH	Strong	Biomarker	[6]
Primary biliary cholangitis	DIS43E0O	Strong	Genetic Variation	[9]
Rheumatoid arthritis	DISTSB4J	Strong	Altered Expression	[10]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[1]
Systemic lupus erythematosus	DISI1SZ7	Strong	Genetic Variation	[11]
Systemic sclerosis	DISF44L6	Strong	Genetic Variation	[12]
Vitiligo	DISR05SL	Strong	Genetic Variation	[13]
Zika virus infection	DISQUCTY	Strong	Biomarker	[14]
Adult glioblastoma	DISVP4LU	moderate	Biomarker	[15]
Autoimmune disease	DISORMTM	moderate	Genetic Variation	[16]
Glioblastoma multiforme	DISK8246	moderate	Biomarker	[15]
Immune system disorder	DISAEGPH	moderate	Genetic Variation	[16]
Syndromic intellectual disability	DISH7SDF	Supportive	Autosomal dominant	[6]
Kaposi sarcoma	DISC1H1Z	Disputed	Biomarker	[17]
Adult lymphoma	DISK8IZR	Limited	Genetic Variation	[18]
Advanced cancer	DISAT1Z9	Limited	Altered Expression	[1]
Colorectal carcinoma	DIS5PYL0	Limited	Biomarker	[1]
Lymphoma	DISN6V4S	Limited	Genetic Variation	[18]
MALT lymphoma	DIS1AVVE	Limited	Biomarker	[19]
Myotonic dystrophy	DISNBEMX	Limited	Altered Expression	[20]
Myotonic dystrophy type 1	DISJC0OX	Limited	Altered Expression	[20]
Nodal marginal zone lymphoma	DIS7MP4T	Limited	Biomarker	[19]
Pediatric lymphoma	DIS51BK2	Limited	Genetic Variation	[18]

10 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 Probable ATP-dependent RNA helicase DDX6 (DDX6).	[21]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Probable ATP-dependent RNA helicase DDX6 (DDX6).	[22]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Probable ATP-dependent RNA helicase DDX6 (DDX6).	[23]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Probable ATP-dependent RNA helicase DDX6 (DDX6).	[24]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Probable ATP-dependent RNA helicase DDX6 (DDX6).	[25]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Probable ATP-dependent RNA helicase DDX6 (DDX6).	[26]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Probable ATP-dependent RNA helicase DDX6 (DDX6).	[27]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Probable ATP-dependent RNA helicase DDX6 (DDX6).	[28]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Probable ATP-dependent RNA helicase DDX6 (DDX6).	[29]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Probable ATP-dependent RNA helicase DDX6 (DDX6).	[30]

References

• [1] Oncogene RNA helicase DDX6 promotes the process of c-Myc expression in gastric cancer cells.Mol Carcinog. 2018 May;57(5):579-589. doi: 10.1002/mc.22781. Epub 2018 Jan 30.
• [2] Quantitative mass spectrometry of DENV-2 RNA-interacting proteins reveals that the DEAD-box RNA helicase DDX6 binds the DB1 and DB2 3' UTR structures.RNA Biol. 2011 Nov-Dec;8(6):1173-86. doi: 10.4161/rna.8.6.17836. Epub 2011 Nov 1.
• [3] Functional analysis of the 11q23.3 glioma susceptibility locus implicates PHLDB1 and DDX6 in glioma susceptibility.Sci Rep. 2015 Nov 27;5:17367. doi: 10.1038/srep17367.
• [4] The RCK gene associated with t(11;14) translocation is distinct from the MLL/ALL-1 gene with t(4;11) and t(11;19) translocations.Cancer Res. 1992 Nov 1;52(21):6083-7.
• [5] Cellular DEAD-box RNA helicase DDX6 modulates interaction of miR-122 with the 5' untranslated region of hepatitis C virus RNA.Virology. 2017 Jul;507:231-241. doi: 10.1016/j.virol.2017.04.014. Epub 2017 Apr 26.
• [6] Rare De Novo Missense Variants in RNA Helicase DDX6 Cause Intellectual Disability and Dysmorphic Features and Lead to P-Body Defects and RNA Dysregulation. Am J Hum Genet. 2019 Sep 5;105(3):509-525. doi: 10.1016/j.ajhg.2019.07.010. Epub 2019 Aug 15.
• [7] The genomic relationship between primary breast carcinomas and their nodal metastases.Cancer Invest. 2011 May;29(4):300-7. doi: 10.3109/07357907.2011.568564.
• [8] Regulation of epithelial-mesenchymal transition and metastasis by TGF-, P-bodies, and autophagy.Oncotarget. 2017 Oct 17;8(61):103302-103314. doi: 10.18632/oncotarget.21871. eCollection 2017 Nov 28.
• [9] Dense fine-mapping study identifies new susceptibility loci for primary biliary cirrhosis.Nat Genet. 2012 Oct;44(10):1137-41. doi: 10.1038/ng.2395. Epub 2012 Sep 9.
• [10] P54/nrb prompts rheumatoid arthritis progression mainly by transcriptionally activating NF-B signaling.Pharmazie. 2017 May 1;72(5):260-264. doi: 10.1691/ph.2017.6904.
• [11] Three SNPs in chromosome 11q23.3 are independently associated with systemic lupus erythematosus in Asians.Hum Mol Genet. 2014 Jan 15;23(2):524-33. doi: 10.1093/hmg/ddt424. Epub 2013 Sep 2.
• [12] GWAS for systemic sclerosis identifies multiple risk loci and highlights fibrotic and vasculopathy pathways.Nat Commun. 2019 Oct 31;10(1):4955. doi: 10.1038/s41467-019-12760-y.
• [13] An in-depth analysis identifies two new independent signals in 11q23.3 associated with vitiligo in the Chinese Han population.J Dermatol Sci. 2017 Oct;88(1):103-109. doi: 10.1016/j.jdermsci.2017.05.001. Epub 2017 May 3.
• [14] Zika virus noncoding sfRNAs sequester multiple host-derived RNA-binding proteins and modulate mRNA decay and splicing during infection.J Biol Chem. 2019 Nov 1;294(44):16282-16296. doi: 10.1074/jbc.RA119.009129. Epub 2019 Sep 13.
• [15] Involvement of DDX6 gene in radio- and chemoresistance in glioblastoma.Int J Oncol. 2016 Mar;48(3):1053-62. doi: 10.3892/ijo.2016.3328. Epub 2016 Jan 11.
• [16] Meta-analysis of genome-wide association studies in celiac disease and rheumatoid arthritis identifies fourteen non-HLA shared loci.PLoS Genet. 2011 Feb;7(2):e1002004. doi: 10.1371/journal.pgen.1002004. Epub 2011 Feb 24.
• [17] KSHV RNA-binding protein ORF57 inhibits P-body formation to promote viral multiplication by interaction with Ago2 and GW182.Nucleic Acids Res. 2019 Sep 26;47(17):9368-9385. doi: 10.1093/nar/gkz683.
• [18] Cloning and expression of a murine cDNA homologous to the human RCK/P54, a lymphoma-linked chromosomal translocation junction gene on 11q23.Gene. 1995 Dec 12;166(2):293-6. doi: 10.1016/0378-1119(95)00559-5.
• [19] t(11;14)(q23;q32) involving IGH and DDX6 in nodal marginal zone lymphoma.Genes Chromosomes Cancer. 2013 Jan;52(1):33-43. doi: 10.1002/gcc.22004. Epub 2012 Sep 11.
• [20] DDX6 regulates sequestered nuclear CUG-expanded DMPK-mRNA in dystrophia myotonica type 1.Nucleic Acids Res. 2014 Jun;42(11):7186-200. doi: 10.1093/nar/gku352. Epub 2014 May 3.
• [21] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [22] 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.
• [23] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [24] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [25] 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.
• [26] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [27] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [28] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [29] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.
• [30] 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.